WO2015041534A1 - P90rsk en combinaison avec raf/erk/mek - Google Patents

P90rsk en combinaison avec raf/erk/mek Download PDF

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WO2015041534A1
WO2015041534A1 PCT/NL2014/050649 NL2014050649W WO2015041534A1 WO 2015041534 A1 WO2015041534 A1 WO 2015041534A1 NL 2014050649 W NL2014050649 W NL 2014050649W WO 2015041534 A1 WO2015041534 A1 WO 2015041534A1
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inhibitor
erk
cancer
nras
p90rsk
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PCT/NL2014/050649
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Daniel Simon Peeper
Marjon Antoinetta SMIT
Celia Jill VOGEL
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Stichting Het Nederlands Kanker Instituut
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the current disclosure relates to pharmaceutical combinations and compositions useful in the treatment of certain types of cancer.
  • the disclosure also relates to method of treatment these certain types of cancer.
  • the disclosure relates to the combined use of an inhibitor of p90RSK and an inhibitor of another protein of the MAPK/ERK-pathway in the treatment of KRAS-, NRAS- or BRAF-mutated cancer, in particular in NRAS mutated melanoma.
  • Cancer cells are by definition heterogeneous. For example, multiple mutational mechanisms may lead to the development of cancer and mutational mechanisms associated with some cancers may differ between one tissue type and another; it is therefore often difficult to predict whether a specific cancer will respond to a specific chemotherapeutic (Cancer Medicine, 5th edition, Bast et al, B. C. Decker Inc., Hamilton, Ontario).
  • the treatment of cancer is gradually changing from an organ-centered to a
  • Non Small Cell Lung Cancer NSCLC
  • NRAS-mutated cancer for example NRAS-mutated melanoma are limited.
  • Figure 1 Combination treatment of p90RSK inhibitor with MEK inhibitor kills or inhibits NRAS mutant melanoma cell proliferation.
  • Cells were seeded equal densities and treated with GSK1120212 (MEKi) and BI-1870 (p90RSK inhibitor) as indicated and stained with crystal violet.
  • MEKi GSK1120212
  • BI-1870 p90RSK inhibitor
  • Figure 2 Combination treatment of p90RSK inhibitor with ERK inhibitor kills or inhibits NRAS mutant melanoma cell proliferation.
  • Cells were seeded at equal densities and treated with SCH772984 (ERKi) and BI-1870 (p90RSK inhibitor) as indicated and stained with crystal violet.
  • ERKi SCH772984
  • BI-1870 p90RSK inhibitor
  • Figure 3 Combination treatment of p90RSK inhibitor with ERK inhibitor kills or inhibits BRAF mutant melanoma cell proliferation.
  • Cells were seeded at equal densities and treated with SCH772984 (ERKi) and BI-1870 (p90RSK inhibitor) as indicated and stained with crystal violet.
  • Figure 4 Combination treatment of p90RSK inhibitor with ERK inhibitor kills or inhibits ERK inhibitor resistant NRAS mutant melanoma cell proliferation.
  • Cells were seeded at equal densities and treated with SCH772984 (ERKi) and BI-1870 (p90RSK inhibitor) as indicated and stained with crystal violet.
  • FIG. 5 Combination treatment of p90RSK inhibitor with MEK inhibitor kills or inhibits proliferation of ERK inhibitor resistant NRAS mutant melanoma cells.
  • Cells were seeded at equal densities and treated with GSK1120212 (MEKi) and BI-1870 (p90RSK inhibitor) as indicated and stained with crystal violet.
  • MEKi GSK1120212
  • BI-1870 p90RSK inhibitor
  • FIG. 6 ERK inhibitor resistant NRAS mutant melanoma cells reactivate MAPK/ERK signaling in the presence of ERK inhibitor.
  • Cells were treated with SCH772984 (ERKi) or vehicle control as indicated, lysed and probed for MAPK/ERK signaling and AKT.
  • a method for administrating a drug includes the administrating of a plurality of molecules (e.g. 10's, 100's, 1000's, 10's of thousands, 100's of thousands, millions, or more molecules).
  • the term "at least" a particular value means that particular value or more.
  • “at least 2” is understood to be the same as “2 or more” i.e., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, etc.
  • cancer and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth.
  • Primary cancer cells can be distinguished from non-cancerous cells by techniques known to the skilled person.
  • a cancer cell includes not only primary cancer cells, but also cancer ceils derived from such primary cancer cell, including metastasized cancer cells, and ceil lines derived from cancer ceils.
  • tumors may metastasize from a first locus to one or more other body tissues or sites.
  • Reference to treatment for a "neoplasm,” “tumor” or “cancer” in a patient includes treatment of the primary cancer, and, where appropriate, treatment of metastases.
  • "in combination with” is intended to refer to all forms of administration that provide a first drug together with a further (second, third) drug.
  • the drugs may be administered simultaneous, separate or sequential and in any order. Drugs administered in combination have biological activity in the subject to which the drugs are delivered.
  • a combination thus comprises at least two different drugs, and wherein one drug is at least a p90RSK- inhibitor and wherein the other drug is at least an inhibitor of another protein of the APK/ERK pathway, as disclosed herein in detail.
  • the p90RSK-inhibitor is a selective inhibitor, and does preferably does not inhibit the "another protein of the MAPK/ERK pathway", as disclosed herein in detail.
  • the inhibitor of another protein of the APK-'ERK pathway is a selective inhibitor, and within the context of the current invention, does not inhibit p90RSK.
  • both the p90RSK-inhibitor and the inhibitor of "another protein of the MAPK/ERK pathway", as disclosed herein in detail are selective inhibitors./V'pct
  • compositions useful in the methods of the present disclosure include those suitable for various routes of administration, including, but not limited to, intravenous, subcutaneous, intradermal, subdermal, intranodal, intratumoral, intramuscular, intraperitoneal, oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral or mucosal application.
  • compositions, formulations, and products according to the disclosure invention normally comprise the drugs (alone or in combination) and one or more suitable pharmaceutically acceptable excipients or carriers.
  • agent/pharmaceutical compound required to ameliorate the symptoms of a disease relative to an untreated patient.
  • the effective amount of active agent(s) used to practice the present invention for therapeutic treatment of a cancer varies depending upon the manner of administration, the age, body weight, and general health of the subject.
  • an effective amount is referred to as an "effective" amount.
  • a drug which, in the context of the current disclosure, is "effective against” a disease or condition indicates that administration in a clinically appropriate manner results in a beneficial effect for at least a statistically significant fraction of patients, such as an improvement of symptoms, a cure, a reduction in at least one disease sign or symptom, extension of life, improvement in quality of life, or other effect generally recognized as positive by medical doctors familiar with treating the particular type of disease or condition.
  • inhibitor of a (defined) protein for example ERK
  • ERK refers to any compound capable of down-regulating, decreasing, suppressing or otherwise regulating the amount and/or activity of the (defined) protein, for example
  • the inhibitors to be used in accordance with the present invention may be selective inhibitors of said (defined) protein; the term "selective” or “selectivity” expresses the biologic fact that at a given compound concentration enzymes (or proteins) are affected to different degrees.
  • selective inhibition can be defined as preferred inhibition by a compound at a given concentration. in other words, an enzyme is selectively inhibited over another enzyme when there is a concentration which results in inhibition of the first enzyme whereas the second enzyme is not affected.
  • an enzyme is selectively inhibited over another enzyme when there is a concentration which results in inhibition of the first enzyme whereas the second enzyme is not affected.
  • Assay formats are readily available in the prior art.
  • the different drugs used in the combination may be drugs that selectively inhibit one of the proteins to be inhibited according to the invention in comparison to the other protein(s), for example when used in a clinical setting.
  • mice, rats and guinea pigs, and the like including, without limitation, humans and non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, sheep, pigs, goats and horses; domestic mammals such as dogs and cats; laboratory animals including rodents such as mice, rats and guinea pigs, and the like.
  • the term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be included within the scope of this term.
  • the mammal is human.
  • “Pharmaceutically acceptable” is employed herein to refer to those combinations of a therapeutic as described herein, other drugs or therapeutics, materials,
  • compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals, without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically-acceptable carrier”, as used herein, means a
  • protein or “polypeptide” are used interchangeably and refer to molecules consisting of a chain of amino acids, without reference to a specific mode of action, size, 3 dimensional structure or origin. A "fragment” or “portion” of a protein may thus still be referred to as a "protein".
  • isolated protein is used to refer to a protein which is no longer in its natural environment, for example in vitro or in a recombinant bacterial or plant host ceil.
  • spontaneous administration refers to administration of more than one drug at the same time, but not necessarily via the same route of administration or in the form of one combined formulation.
  • one drug may be provided orally whereas the other drug may be provided intravenously during a patients visit to a hospital.
  • Separatate administration includes the administration of the drugs in separate form and/or at separate moments in time, but again, not necessarily via the same route of administration.
  • subsequentially of “sequential administration” indicates that the administration of a first drug if followed, immediately or in time, by the administration of the second drug.
  • small molecule is understood to refer to a chemical compound having a molecular weight below 2,500 Daitons, more preferably between 300 and 1 ,500 Daltons, and still more preferably between 400 and 1000 Daitons. it is preferred that these small molecules are organic molecules. In certain embodiments, "small molecule” does not include peptide or nucleic acid molecules.
  • subject is intended to include vertebrates, preferably a mammal, including human and non-human mammals such as non-human primates. Human subjects are can be referred to as patients.
  • treating a disorder or condition does not require that the disorder, condition or symptoms associated therewith be completely eliminated.
  • wild type refers to a polypeptide
  • a "mutant" includes a polypeptide or polynucleotide sequence having at least one modification to an amino acid or nucleic acid compared to the corresponding amino acid or nucleic acid found in a wild type polypeptide or polynucleotide, respectively.
  • Cancers that are either wild type or mutant for NRAS, KRAS or BRAF are identified by known methods.
  • wild type or mutant NRAS/BRAF/KRAS cancer cells can be identified by DNA amplification and sequencing techniques, DNA and RNA detection techniques, including, but not limited to Northern and Southern blot, respectively, and/or various biochip and array technologies.
  • Wild type and mutant polypeptides can be detected by a variety of techniques including, but not limited to immunodiagnostic techniques such as ELISA, or Western blot. Mutation tests are, for example, available via fttp://therapy. collabrx.com/melanoma/molecular_analysis/ (as per 27 July 2013).
  • the current disclosure is based on the surprising finding that a combination of an inhibitor of the protein (enzyme) p90RSK and at least one inhibitor of another protein of the MAPK ERK pathway is synergistic, i.e. produces an effect greater than the effect of the individual drugs, or even greater than the sum of the their individual effects, in inhibiting proliferation of or inducing apoptosis in a cancer in a mammal, preferably a human, wherein the cancer is selected from the group consisting of NRAS-, KRAS- and BRAF-mutated cancer, preferably NRAS-mutated cancer, for example, but not limited to NRAS-, KRAS- and BRAF-mutated melanoma, for example NRAS-mutated melanoma or lung cancer.
  • the inhibitors in the combination may, in one embodiment be selective inhibitors (or a selective inhibitor).
  • the claimed combination works also in those cells that are relatively insensitive to inhibition by the other inhibitor of a protein of the MAPK/ERK pathway alone (e.g. a RAF-inhibitor alone, an ERK-inhibitor alone, a MEK-inhibitor alone, or a p90RSK-inhibitor alone).
  • Such cells are also referred to as resistant cancer cells and do not normally respond to treatment.
  • the cancer may be resistant at the beginning of treatment (often called intrinsic resistance), or it may become resistant during treatment (also called refractory cancer) (often called acquired resistance.
  • the cancer is a NRAS-, KRAS- and BRAF-mutated cancer, preferably melanoma, that is or has become relatively insensitive or resistant to the other inhibitor (i.e. not a p90RSK inhibitor) of a protein of the
  • MAPK/ERK-pathway preferably, that has become relatively insensitive or resistant to an ERK-inhibitor, a MEK-inhibitor, and/or a RAF-inhibitor, i.e. has or acquired resistance.
  • the term "acquired resistance" indicates that the cancer becomes resistant to the effects of the drug after being exposed to it for a certain period of time.
  • the inventors of the present invention have demonstrated, via experiments, that the combination of a p90RSK-inhibitor and at least one inhibitor of another protein of the MAPK/ERK pathway, for example a MEK-inhibitor, a ERK-inhibitor, and/or a RAF- inhibitor manifests an unexpected and strong synergistic, therapeutic effect on the treatment of NRAS-, KRAS- and BRAF-mutated cancer, preferably NRAS-mutated cancer, for example, NRAS-mutated melanoma.
  • the invention thus provides for improved treatment strategies by employing the combination at least two different drugs or compounds, directed to inhibiting the combination of proteins/enzymes as disclosed herein.
  • the dose of each of the drugs in the combination may be optimized in order to achieve optimal treatment effect.
  • the individual dose of a first individual drug in the combination may be optimized to achieve optimal inhibition of a first protein, and a second, third or further drug in the combination may be optimized to achieve optimal inhibition of the other protein/enzyme to be inhibited, and as detailed herein.
  • the invention allows for the treatment with various and different combinations of inhibitors of the proteins/enzymes to be inhibited, as detailed herein.
  • the current invention allows for the replacement of a drug in such combination, or of the combination by another drug combination, in accordance with the invention and in order to overcome undesired effects or, again optimize treatment of the patient.
  • the current invention allows for the replacement of a drug in such combination, or of the combination by another drug combination, in accordance with the invention and in order to overcome undesired effects or, again optimize treatment of the patient.
  • the dose of the individual drugs may be lowered compared to when the drugs are used individually, which may be beneficial in view of toxicity.
  • the combination disclosed herein exhibits (therapeutic) co-operation and/or synergy when used to treat a subject or patient. Such effect may be demonstrated by the showing that the combination is superior to one or other of the constituents used as at a given, for example, optimum dose.
  • the combination therapy disclosed herein is particular suitable for use in patients that carry mutations in the genes encoding a RAS protein and/or BRAF protein, leading to proteins with aberrant function.
  • RAS protein means any protein which is a member of the ras-subfamily, a subfamily of GTPases involved in cellular signaling. As is known in the art, activation of RAS causes cell growth, differentiation and survival.
  • RAS proteins include, but are not limited to, HRAS, KRAS and NRAS. The proteins differ significantly only in the C-terminal 40 amino acids.
  • RAS proteins are normally tightly regulated by guanine nucleotide exchange factors (GEFs) promoting GDP dissociation and GTP binding and GTPase-activating proteins (GAPs) that stimulate the intrinsic GEFs.
  • GEFs guanine nucleotide exchange factors
  • GAPs GTPase-activating proteins
  • KRAS-mutated (also referred to as or KRAS-mutant) cancer and in a preferred embodiment particular useful in patients that are characterized by having a KRAS- mutant melanoma.
  • KRAS-mutated cancer and thus KRAS-mutated melanoma are well known to the skilled person.
  • a comprehensive overview of RAS mutations, including KRAS-mutations, in cancer was reported by Prior et al (2012) Cancer Res; 2457 - 67, KRAS-mutant cells promote oncogenesis due to being mutationaliy activated, in most cases, at codon 12, 13 and 61. In total forty-four separate point mutations have been characterized in RAS isoforms, with 99.2% in codons 12, 13 and 61.
  • the protein product of the normal KRAS gene performs an essential function in normal tissue signaling, and the mutation of a KRAS gene is an essential step in the development of many cancers.
  • the GTPase KRAS also known as V-Ki-ras2 Kirsten rat sarcoma viral oncogene homo!og or KRAS, is a protein that in humans is encoded by the KRAS gene (e.g. Gene accession number 3845; Refseq RNA Accessions NM_004985.3; protein NP_004976.2).
  • the KRAS protein is a GTPase and is an early player in many signal transduction pathways. KRAS acts as a molecular on/off switch. Once it is turned on it recruits and activates proteins necessary for the propagation of growth factor and other receptors' signal, such as c-Raf and PI 3-kinase.
  • the combination therapy disclosed herein is for use in patients with NRAS-mutated (also referred to as or NRAS-mutant) cancer, and in a preferred embodiment particular useful in patients that are characterized by having a NRAS-mutated melanoma.
  • NRAS-mutated cancer also referred to as or NRAS-mutant
  • the term "NRAS-mutated cancer” and therefore NRAS- mutated melanoma are well known to the skilled person.
  • a comprehensive overview of RAS mutations, including NRAS-mutations, in cancer was reported by Prior et al (2012) Cancer Res; 2457 - 67.
  • NRAS-mutant cells promote ontogenesis due to being mutationaliy activated, in most cases, again at codon 12, 13 and 61.
  • the NRAS protein is a GTPase enzyme that in humans is encoded by NRAS (neuroblastoma RAS viral (v-ras) oncogene homolog) gene (e.g. Gene accession number 4893; Refseq RNA Accessions N J302524.4; protein NPJ3Q2515.1).
  • NRAS nerveroblastoma RAS viral (v-ras) oncogene homolog
  • the N-ras gene specifies two main transcripts of 2Kb and 4.3Kb, both transcripts appear to encode identical proteins as they differ only in the 3' untranslated region.
  • BRAF-mutated (also referred to as or BRAF-mutant) cancer and in a preferred embodiment particular useful in patients that are characterized by having a BRAF- mutant melanoma.
  • the term "BRAF-mutated cancer” and therefore BRAF-mutated melanoma are well known to the skilled person.
  • BRAF e.g. Gene accession number 673; Refseq RNA Accessions NM_004333.4; protein NP_004324.2
  • BRAF is a member of the RAF family, which includes ARAF and CRAF in humans (Ikawa, Mol Cell Biol. 8(6):2651- 4 (1988)).
  • BRAF is a serine/threonine protein kinase and participates in the
  • Such mutation in BRAF typically leads to proliferation and survival of melanoma cells (Davies et al Nature 2002; 417:949-54; Curtin et al N Engl J Med 2005;353:2135-47), through activation of the MAPK/ERK pathway.
  • this pathway plays a significant role in modulating cellular responses to extracellular stimuli, particularly in response to growth factors, and the pathway controls cellular events including cell proliferation, cell-cycle arrest, terminal differentiation and apoptosis (Peyssonnaux et al., Biol Cell. 93(l-2):53-62 (2001)).
  • the disclosed combination comprises a p90RSK-inhibitor and at least one
  • a p90RSK polypeptide (e.g. EC 2.7.1 1.1 ; e.g. Gene accession numbers 6195, 6197, 6196, or 27330; Refseq RNA Accessions NM_0Q 1006665, NM_0Q2953,
  • protein or peptide is to indicate a protein of the ribosomal s6 kinase (rsk) a family of protein kinases.
  • rsk ribosomal s6 kinase
  • p90RSK also known as MAPK-activated protein kinase-1 (MAPKAP- K1)
  • p70RSK also known as S6-H1 Kinase or simply S6 Kinase.
  • RSK 1- 4 are serine/threonine kinases and are activated by the MAPK/ERK pathway.
  • the RSK protein is a MAP kinase activated protein kinase (MAPKAP kinase) and described in, e.g., Leukemia, 17: 1263-1293 (2003).
  • p90RSK is phosphorylated and activated by Erk1 and -2 in response to many growth factors, polypeptide hormones and neurotransmitters.
  • RSK has been shown to directly promote cell survival by regulating the expression and activation of pro-survival proteins such as CREB (cyclic adenosine monophosphate response element binding protein).
  • CREB cyclic adenosine monophosphate response element binding protein
  • p90RSK biological activity is meant any function of p90RSK, such as herein.
  • p90RSK inhibitor is meant a compound that reduces the biological activity of p90RSK; or that reduces the expression of an mRNA encoding ap90RSK polypeptide; or that reduces the expression of a p90RSK polypeptide.
  • an "effective amount of an inhibitor" e.g. an “effective amount of a p90RSK inhibitor” is the amount of inhibitor required to inhibit expression of, in the case of p90RSK, p90RSK or inhibit activity of p90RSK.
  • the inhibitor may, in one embodiment, be a selective inhibitor.
  • p90RSK inhibitors include, for example, Kaempherol-3-0-(4'-0-acetyl-a-L- rhamnopyranoside), or those disclosed in EP1845778. Further examples are provided in the Table 1 below.
  • the activity of RSK protein or inhibitory activity of a p90RSK inhibitor can be determined by the method described in, e.g., EMBO J., 14: 674-684 (1995) or in EP1845778.
  • the p90RSK inhibitor may inhibit (gene) expression of p90RSK, for example by interfering with mRNA stability or translation.
  • the p90RSK inhibitor is selected from small interfering RNA (siRNA), which is sometimes known as short interfering RNA or silencing RNA, or short hairpin RNA (shRNA), which is sometimes known as small hairpin RNA.
  • siRNA small interfering RNA
  • shRNA short hairpin RNA
  • the p90RSK inhibitor according to the present invention may be a binding agent such as an antibody which specifically binds p90RSK, thereby inhibiting its function.
  • the inhibitor of the another protein of the MAPK/ERK pathway may be any one of the MAPK/ERK pathway.
  • inhibitor that reduces the activity of one or more proteins that belong to the MAPK/ERK pathway.
  • MAPK/ERK pathway is well-known to the skilled person and is one of the four parallel mitogen activated protein kinase (MAPK) signaling pathways identified:
  • the pathways are involved in cellular events such as growth, differentiation and stress responses (J. Biol. Chem. (1993) 268, 14553-14556). These four pathways are linear kinase cascades in that MAPKKK phosphorylates and activates MAPKK, and MAPKK phosphorylates and activates MAPK. To date, seven MAPKK homologs (MEK1 ,
  • MAPK2 MKK2, MKK3, MKK4/SEK, MEK5, MKK6, and MKK7 and four MAPK families (ERK1/2, JNK, p38, and ERK5) have been identified. Activation of these pathways regulates the activity of a number of substrates through phosphorylation. These substrates include: transcription factors such as TCF, c-myc, ATF2 and the AP-1 components, fos and Jun; cell surface components EGF-R; cytosolic components including PHAS-I, p90rsk, cPLA2 and c-Raf-1 ; and cytoskeleton components such as tau and MAP2.
  • MAPK signaling cascades are involved in controlling cellular processes including proliferation, differentiation, apoptosis, and stress responses.
  • the MAPK/ERK pathway (also referred to as RAF-MEK-ERK pathway or Ras-Raf-MEK-ERK pathway) mediates proliferative and anti-apoptotic signaling from growth factors and oncogenic factors such as Ras and Raf mutant phenotypes that promote tumor growth, progression, and metastasis.
  • the MAPK/ERK pathway provides molecular targets with potentially broad therapeutic applications in, for example, cancerous and noon- cancerous hyperproliferative disorders, immunomodulation and inflammation.
  • a protein of the MAPK/ERK pathway includes ERK, MEK, RAF, and RSK proteins, as discussed below.
  • the protein of the MAPK/ERK pathway is selected from the group consisting of RAF, MEK, and ERK, and combination of two or three thereof.
  • the inhibitor of the another protein of the MAPK/ERK pathway is selected from the group consisting of a RAF-inhibitor, an ERK- inhibitor, and a MEK-inhibitor.
  • more than one inhibitor of a protein of the MAPK/ERK pathway is used.
  • two, three or four inhibitors of one or more proteins of the MAPK/ERK pathway are used in the combination therapy disclosed herein, i.e. in combination with a p90RSK inhibitor or one, two, three or more p90RSK inhibitors.
  • at least one p90RSK-inhibitor may be combined with at least one MEK- inhibitor and/or at least one ERK-inhibitor, and/or at least one RAF inhibitor.
  • a RAF protein, polypeptide or peptide is to indicate a polypeptide having
  • RAF kinases are a family of three
  • ARAF ARAF
  • BRAF BRAF
  • CRAF CRAF
  • BRAF for example, Genbank Accession NO: NP004324
  • BRAF phosphorylates and activates MEK (MEK1 and MEK2).
  • MEK1 and MEK2 MEK2 and MEK2.
  • BRAF is a member of the RAF family, which includes ARAF and CRAF in humans (Ikawa, Mol Cell Biol.
  • BRAF is a serine/threonine protein kinase and participates in the RAS/RAF/MEK/ERK mitogen activated protein kinase pathway (MAPK pathway, see Williams & Roberts, Cancer Metastasis Rev. 13(1): 105-16 (1994); Fecher et al 2008 Curr Opin Oncol 20, 183-189).
  • CRAF e.g. Gene accession number 5894; Refseq RNA Accessions
  • NM_002880.3; protein NPJ3G2871.1) acts as a MAP3 kinase, initiating the entire kinase cascade of the MAPK/ERK pathway.
  • RAF biological activity is meant any function of RAF, such as enzymatic
  • RAF inhibitor for example a BRAF inhibitor, is meant a compound that
  • RAF kinase inhibitors as used herein include efficient inhibitors of RAF kinase, particularly CRAF kinase inhibitors and wild and mutated BRAF kinase inhibitors, e.g. including inhibitors of mutant BRAF kinase.
  • RAF kinase inhibitors e.g. low molecular compounds
  • Any RAF inhibitor including any pharmaceutical agent having RAF inhibitory activity or selective RAF inhibitors may be utilized in the present invention. Examples of
  • RAF kinase inhibitors include the compounds GW5074, BAY 43-9006, CHIR-265, and compounds as defined in US 6,987,1 19, WO98022103, WO99032436,
  • BRAF inhibitors are described, for instance, in WO 2010/114928, WO 2005/123696, WO2007/002325, WO 2006/003378, WO 2006/024834, WO 2006/024836, WO 2006/040568, WO
  • Preferred RAF inhibitors include Vemurafenib, PLX4720 (Tsai et al. 2008 PNAS 105(8):3041) , PLX4032 (RG7204), GDC-0879 (Klaus P. Hoeflich et al. Cancer
  • Sorafenib Tosylate e.g. from Bayer and Onyx
  • dasatinib also known as BMS-354825, e.g. as produced by Bristol-Myers Squibb and sold under the trade name Sprycel
  • erlotinib e.g. as marketed by Genentech and OSI pharmaceuticals as Tarceva
  • LGX818 from Novartis
  • Dabrafenib TefinlarTM capsule, made by GlaxoSmithKline, LLC
  • the derivative of the BRAF inhibitor is a salt.
  • the RAF inhibitor may be selected from the group consisting of dasatinib, erlotinib hydrochloride, dabrafenib, gefitinib, imatinib mesilate, lapatinib, sorafenib tosylate and sunitinib malate.
  • the RAF inhibitor is sorafenib tosylate.
  • Vemurafenib also known as PLX4032, RG7204 or R05185426, e.g. marketed as Zelboraf, from Plexxikon (Daiichi Sankyo group) and Hoffmann-La
  • the RAF inhibitor is selected from any one of the BRAF
  • RAF inhibitors disclosed in WO2006/024834, W02006/067446, PCT/GB2006/004756 or is selected from any one of CHIR-265 (Novartis), XL281 (Exelixis) or PLX4032 (Plexxikon, or Roche).
  • the RAF inhibitor is selected from any one of the BRAF inhibitors disclosed in WO2008120004.
  • BRAF inhibitors include GSK21 18436, benzenesulfonamide, N-[3-[5-(2-amino-4-pyrimidinyl)-2-(1 , 1-dimethylethyl)-4-thiazolyl]- 2-fluorophenyl]-2,6-difluoro-, methanesulfonate (1 : 1), N- ⁇ 3-[5-(2-aminopyrimidin-4-yl)-2- (1 , 1-dimethylethyl)thiazol-4-yl]-2-fluorophenyl ⁇ -2,6- difluorobenzenesulfonamide monomethanesulfonate (Clin Cancer Res. 201 1 ; doi: 10.1158/1078-0432;
  • the RAF inhibitor is a small interfering nucleotide
  • RAF activity in a cell can be decreased or knocked down by exposing (once or repeatedly) the cell to an effective amount of the appropriate small interfering nucleotide sequence.
  • the skilled person knows how to design such small interfering nucleotide sequence, for example as described in handbooks such as Doran and Helliwell RNA interference: methods for plants and animals Volume 10 CABI 2009.
  • a variety of techniques can be used to assess interference with RAF activity of such small interfering nucleotide sequence, such as described in WO 2005/047542, for example by determining whether the candidate small interfering nucleotide sequence decreases BRAF activity.
  • Candidate small interfering nucleotide sequences that are capable of interference may be selected to further analysis to determine whether they also inhibit proliferation of melanoma cells, for example by assessing whether changes associated with inhibition of proliferation of melanoma cells occurs in melanoma cells.
  • the RAF inhibitor according to the present invention may be a binding agent such as an antibody which specifically binds activated and/or mutated BRAF such as the ones described in WO 2005/047542, or as described in US 2004/0096855.
  • a RAF inhibitor has RAF inhibitor activity, or in other words reduces activated (or mutated) RAF activity, which activity may be verified by method known to the skilled person, for example those disclosed in EP0986382B1.
  • a ERK polypeptide or peptide is to indicate a polypeptide having serine/threonine protein kinase activity, e.g. ERK phosphorylates and activates MAP (microtubule- associated proteins), and having at least 85% amino acid identity to the amino acid sequence of a human ERK, e.g ERK1 (e.g. Gene accession number 5595; Refseq RNA Accessions NM_001040056.2; protein NP_Q0 035145.1) or ERK2 (e.g. Gene accession number 5594; Refseq RNA Accessions NM_002745.4; protein NP_002736.3).
  • ERK1 e.g. Gene accession number 5595; Refseq RNA Accessions NM_001040056.2; protein NP_Q0 035145.1
  • ERK2 e.g. Gene accession number 5594; Refseq RNA Accessions NM_00
  • ERK enzymes other proteins mentioned herein, and variations thereof are available in GenBank, accessible via http://www.ncbi.nlm.nih.gov/genbank/ by entering either the numbers mentioned above or entering the relevant protein name.
  • ERK biological activity is meant any function of ERK, such as enzymatic activity, kinase activity, the ability to phosphorylate an ERK substrate, or signaling the MAPK/ERK pathway.
  • ERK inhibitor is meant a compound that reduces the biological activity of ERK; or that reduces the expression of an mRNA encoding an ERK polypeptide; or that reduces the expression of an ERK polypeptide.
  • An ERK inhibitor can inhibit one member, several members or all members of the family of ERK kinases.
  • ERK extracellularly regulated kinase
  • MAP kinases which regulate the growth and proliferation of cells
  • Embodiments of the invention include an ERK inhibitor that inhibits or reduces ERK protein expression, amount of ERK protein or level of ERK translation, amount of ERK transcript or level of ERK transcription, stability of ERK protein or ERK transcript, half-life of ERK protein or ERK transcript, prevents the proper localization of an ERK protein or transcript; reduces or inhibits the availability of ERK polypeptide, reduces or inhibits ERK activity; reduces or inhibits ERK, binds ERK protein, or inhibits or reduces the post-translational modification of ERK, including its phosphorylation.
  • the above described inhibitory action are also to be construed to apply, in comparable fashion to any inhibitor described herein for its specific target (e.g. a BRAF inhibitor for
  • the inhibitor is a selective inhibitor.
  • the ERK inhibitor is an ERK inhibitor such as disclosed in WO2002058687, for example SL-327 (Carr et al
  • the ERK inhibitor is a small interfering nucleotide
  • ERK activity in a cell can be decreased or knocked down by exposing (once or repeatedly) the cell to an effective amount of the appropriate small interfering nucleotide sequence.
  • the skilled person knows how to design such small interfering nucleotide sequence, for example as described in handbooks such as Doran and Helliwell RNA interference: methods for plants and animals Volume 10 CABI 2009.
  • Candidate small interfering nucleotide sequences that are capable of interference may be selected to further analysis to determine whether they also inhibit proliferation of melanoma cells, for example by assessing whether changes associated with inhibition of proliferation of melanoma cells occurs in melanoma cells.
  • analogues, derivatives or modified versions of the above-documented ERK inhibitors may be used in the context of the present invention, as long as such analogues, derivatives or modified versions have ERK inhibitor activity.
  • the ERK inhibitor according to the present invention may be a binding agent such as an antibody which specifically binds ERK, thereby inhibiting its function.
  • ERK inhibitor activity may be assayed in vitro, in vivo or in a cell line.
  • In vitro assays include assays that determine inhibition of either the kinase activity or ATPase activity of activated ERK. Alternate in vitro assays quantitate the ability of the inhibitor to bind to ERK and may be measured either by radiolabelling the inhibitor prior to binding, isolating the inhibitor/ERK complex and determining the amount of radiolabel bound, or by running a competition experiment where new inhibitors are incubated with ERK bound to known radioligands. One may use any type or isoform of ERK, depending upon which ERK type or isoform is to be inhibited. An example of measuring ERK inhibitory activity is described in EP 1317453 B1.
  • a MEK polypeptide e.g. Gene accession numbers 5604 or 5605; Refseq RNA
  • MEK1 e.g. Genbank Accession NO: NP002746
  • MEK2 e.g. Genbank Accession NO: NP109587
  • MAPK MAPK
  • MEK1 and MEK2 MAP/ERK kinase 1 , MEK1 , PRKMK1 , MAPKK1 , MAP2K1 , MKK1 are the same enzyme, known as MEK1 , MAP/ERK kinase 2, MEK2, PRKMK2, MAPKK2, MAP2K2, MKK2 are the same enzyme, known as MEK2.
  • MEK1 and MEK2 together MEK, can phosphorylate serine, threonine and tyrosine residues in protein or peptide substrates. To date, few cellular substrates of MEK isoforms have been identified. The amino acid sequence of MEK enzymes, other proteins mentioned herein, and variations thereof are available in GenBank, accessible via http://www.ncbi.nlm.nih.gov/genbank/ by entering either the numbers mentioned above or entering the relevant protein name.
  • MEK biological activity is meant any function of MEK, such as enzymatic
  • MEK inhibitor is meant a compound that reduces the biological activity of MEK; or that reduces the expression of an mRNA encoding a MEK polypeptide; or that reduces the expression of a MEK polypeptide.
  • a MEK inhibitor can inhibit one member, several members or all members of the family of MEK kinases.
  • the MEK inhibitor is a selective inhibitor.
  • Preferred MEK inhibitors include but are not limited to the MEK inhibitors PD184352 and PD98059, inhibitors of MEK1 and MEK2 U0126 (see Favata, M., et al., Identification of a novel inhibitor of mitogen-activated protein kinase. J. Biol. Chem. 273, 18623, 1998) and SL327 (Carr et al Psychopharmacology (Berl). 2009 Jan;201 (4):495-506), and those MEK inhibitors discussed in Davies et al (2000) (Davies et al Biochem J. 351 , 95-105).
  • PDI 84352 (Allen, Lee et al Seminars in Oncology, Oct. 2003, pp. 105-106, vol. 30) has been found to have a high degree of specificity and potency when compared to other known MEK inhibitors, and may thus be preferred.
  • a preferred MEK inhibitor GSK1 120212/Trametinib (GlaxxoSmithKline) has been approved for treatment of BRAF mutant melanoma under the name Mekinist.
  • MEK162 (Novartis) is also preferred.
  • Other MEK inhibitors and classes of MEK inhibitors are described in Zhang et al. (2000) Bioorganic & Medicinal Chemistry Letters; 10:2825- 2828. [087] Further MEK inhibitors are for example described in Tecle et al Medicinal Chemistry Letters Volume 19, Issue 1 , 1 January 2009, Pages 226-229;
  • WO2008124085 WO2009018233, WO20071 13505, US201 1105521 , WO201 1067356, WO2011067348, US2010004247, and US2010130519.
  • GSK1120212 is an example of a further MEK inhibitor.
  • the MEK inhibitor may also preferably be selected from AZD6244, 4-(4-Bromo-2- fluorophenylamino)-N-(2-hydroxyethoxy)- 1 ,5-dimethyl-6-oxo- 1 ,6-dihydropyridazine-3- carboxamide or 2-(2-fluoro-4-iodophenylamino)-N-(2-hydroxyethoxy)- 1 ,5-dimethyl-6- oxo-l,6-dihydropyridine-3-carboxamide.
  • the MEK inhibitor is selected from AZD6244 or a pharmaceutically acceptable salt thereof.
  • the MEK inhibitor is AZD6244 hydrogen sulphate salt.
  • AZD6244 hydrogen sulphate salt and derivates thereof may be synthesized according to the process described in
  • the MEK inhibitor is selected from 6-(4-Bromo-2-chloro- phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy- ethoxy)-amide or a pharmaceutically acceptable salt thereof.
  • the MEK inhibitor is 6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H- benzoimidazole-5- carboxylic acid (2-hydroxy-ethoxy)-amide hydrogen sulphate salt. 6-
  • the MEK inhibitor may be selected from the group consisting of certain experimental compounds, some of which are currently in
  • Phase 1 or Phase II studies namely PD-325901 (Phase 1 , Pfizer), XL518 (Phase 1 , Genentech), PD-184352 (Allen and Meyer Semin Oncol. 2003 Oct;30(5 Suppl 16): 105- 16.), PD- 318088 (Tecle et al nic & Medicinal Chemistry Letters Volume 19, Issue 1 , 1 January 2009, Pages 226-229), AZD6244 (Phase II, Dana Farber, AstraZeneca) and Cl- 1040 (Lorusso et al Journal of clinical oncology 2005, vol. 23, no23, pp. 5281-5293).
  • the MEK inhibitor is selected from any one of AZD6244
  • Examples of drugs that inhibit MEK include PD-0325901 (Pfizer), AZD-8330
  • TAK-733 TAK733 1035555-63-5 C17H15F2IN404
  • the MEK inhibitor may inhibit (gene) expression of MEK, for example by interfering with mRNA stability or translation.
  • the MEK inhibitor is selected from small interfering RNA (siRNA), which is sometimes known as short interfering RNA or silencing RNA, or short hairpin RNA (shRNA), which is sometimes known as small hairpin RNA.
  • siRNA small interfering RNA
  • shRNA short hairpin RNA
  • the MEK inhibitor according to the present invention may be a binding agent such as an antibody which specifically binds MEK, thereby inhibiting its function.
  • the combination therapy disclosed herein is useful in the treatment of patients having a cancer selected from the group consisting of NRAS-, KRAS- and BRAF- mutated cancers.
  • the combination is in particular useful in the treatment of patients having melanoma, i.e. NRAS-mutated melanoma, KRAS-mutated-melanoma or
  • the combination treatment is for patients with NRAS-mutated melanoma.
  • the cancer e.g. melanoma, e.g. NRAS mutant melanoma
  • the cancer maybe a naive cancer (previously untreated with anti-cancer drugs, e.g. with an inhibitor on the MAPK/ERK pathway; another inhibitor, chemotherapy or Radiation therapy), or may be a cancer that is resistant or acquired resistance as a consequence of prior treatment (e.g. with an inhibitor on the MAPK/ERK pathway; another inhibitor, chemotherapy or Radiation therapy), as can be witnessed from the examples disclosed herein.
  • the findings support a combination therapy of inhibitors of the MAPK/ERK pathway (ERK-, RAF and/or MEK-inhibitors) and p90RSK inhibitors for NRAS, KRAS and/or BRAF mutated cancers, in particular NRAS mutant melanoma, both treatment- naive and with acquired resistance to MAPK/ERK pathway, e.g. ERK pathway, targeting therapies.
  • ERK-, RAF and/or MEK-inhibitors p90RSK inhibitors for NRAS, KRAS and/or BRAF mutated cancers, in particular NRAS mutant melanoma
  • NRAS mutant melanoma both treatment- naive and with acquired resistance to MAPK/ERK pathway, e.g. ERK pathway, targeting therapies.
  • the combination disclosed herein and the use of the disclosed combination in the treatment of the type of cancers disclosed herein may further be combined with other drugs or treatments, for example with (the use of) chemotherapy and/or radio therapy
  • Melanoma is, next to basal cell cancer and squamous cell cancer, one of the three most serious types of skin cancer.
  • Skin cancer is the most commonly diagnosed type of cancer. Although less common than the other two types, melanoma causes the majority (75%) of deaths related to skin cancer (Jerant et al 2000 Am Fam Physician 62 (2): 357-68, 375-6, 381-2).
  • melanoma causes the majority (75%) of deaths related to skin cancer (Jerant et al 2000 Am Fam Physician 62 (2): 357-68, 375-6, 381-2).
  • melanoma cause about 48,000 deaths worldwide per year (Lucas et al 2006 Environmental Bur
  • the first sign of melanoma often is a change in size, shape, color or feel of a mole, which may accordingly have turned into a malignant tumor of melanocytes.
  • the present invention relates to combinations suitable for treating or lessening the severity of melanoma, including subtypes of melanoma such as but not limited to superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral lentiginous melanoma, and choroidal intraocular melanoma, ocular intraocular melanoma, and uveal intraocular melanoma.
  • Melanocytes are cells that normally produce the pigment melanin, which is
  • Melanoma can occur in any part of the body where melanocytes are present.
  • Cutaneous melanomas have mutations in the NRAS GTPase in 15% of cases (NRAS mutated cancer, NRAS mutated melanoma; Kelleher et. al (2012 Cancer J.18(2): 132-136)). Compared to melanomas with BRAF mutations, or melanomas "wild- type" for BRAF and NRAS, melanomas with NRAS mutations are more likely to be thicker tumors and to have a higher mitotic rate. Preclinical studies indicate that melanoma cells with NRAS mutations are dependent on NRAS for survival and proliferation, making NRAS an attractive therapeutic target in melanoma. However, to date, therapeutic strategies for NRAS mutant melanomas have not been realized in the art.
  • the p90RSK-inhibitor is BI-D1870
  • the RAF-inhibitor is selected from the group consisting of PLX4720
  • the ERK-inhibitor is selected from the group consisting of SCH772984 and VTX-11 e, and/or the MEK-inhibitor is selected from the group consisting of GSK1120212 (Trametinib) and MEK162.
  • a p90RSK-inhibitor for use in treatment of a cancer selected from the group consisting of NRAS-, KRAS- and BRAF-mutated cancer, preferably NRAS-mutated cancer, wherein the p90RSK-inhibitor is administrated simultaneously, separately or sequentially with an inhibitor of another protein of the MAPK/ERK pathway.
  • the p90RSK-inhibitor for use in treatment of a cancer selected from the group consisting of NRAS-, KRAS- and BRAF- mutated cancer, preferably NRAS-mutated cancer, wherein said inhibitor of another protein of the MAPK/ERK pathway is selected from the group consisting of a RAF- inhibitor, an ERK-inhibitor and a MEK-inhibitor.
  • RAF-inhibitor for use in treatment of a cancer selected from the group consisting of NRAS-, KRAS- and BRAF-mutated cancer, preferably NRAS-mutated cancer, wherein the RAF-inhibitor is administrated simultaneously, separately or sequentially with a p90RSK-inhibitor.
  • an ERK-inhibitor for use in treatment of a
  • NRAS-, KRAS- and BRAF-mutated cancer selected from the group consisting of NRAS-, KRAS- and BRAF-mutated cancer, preferably NRAS-mutated cancer, wherein the ERK-inhibitor is administrated
  • a MEK-inhibitor for use in treatment of a cancer selected from the group consisting of NRAS-, KRAS- and BRAF-mutated cancer, preferably NRAS-mutated cancer, wherein the MEK-inhibitor is administrated
  • the p90RSK- inhibitor is BI-D1870
  • the RAF-inhibitor is selected from the group consisting of PLX4720
  • the ERK-inhibitor is selected from the group consisting of SCH772984 and VTX-11 e, and/or the MEK-inhibitor is selected from the group consisting of GSK1120212 (Trametinib) and MEK162.
  • the cancer is NRAS mutated melanoma.
  • inhibitors for the combination therapy as disclosed herein may be any inhibitors for the combination therapy as disclosed herein.
  • the product leaflet of the p90RSK-inhibitor may suggest the simultaneous, separate or sequential use of the p90RSK-inhibitor with an inhibitor of the another protein of the MAPK/ERK-pathway, preferably an ERK inhibitor and/or a MEK-inhibitor and/or a RAF-inhibitor.
  • the product leaflet of the inhibitor of another protein of the MAPK/ERK pathway may suggest the simultaneous, separate or sequential use of the inhibitor of a protein of the MAPK/ERK pathway with a p90RSK-inhibitor.
  • the new use of the combination of inhibitors is not limited to combinations administered separately, but also includes the compositions obtained by physical association of the drugs and in either case a synergistic effect is obtained.
  • spontaneous administration refers to administration of more than one drug at the same time, but not necessarily via the same route of administration or in the form of one combined formulation.
  • one drug may be provided orally whereas the other drug may be provided intravenously during a patients visit to a hospital.
  • Separate includes the administration of the drugs in separate form and/or at separate moments in time, but again, not necessarily via the same route of
  • the combination of drugs disclosed herein will preferably be administered to the patient in a form that is suitable for administration to the patient and in a dose that is efficacious, i.e. in an effective amount.
  • the current disclosure thus relates, in these aspects, to a combination therapy, wherein during the therapy the patient is treated with a drug that is an inhibitor of p90RSK in combination with (another) inhibitor that inhibits another protein of the MAPK ERK pathway (i.e. not p90RSK), preferably an ERK-inhibitor, a MEK-inhibitor, and/or a RAF-inhibitor.
  • a product comprising a p90RSK-inhibitor and an inhibitor of another protein of the MAPK/ERK pathway, as a combined preparation for simultaneous, separate or sequential use in treatment of a cancer selected from the group consisting of NRAS-, KRAS- and BRAF-mutated cancer, preferably NRAS-mutated cancer, even more preferably NRAS-mutated melanoma.
  • said inhibitor of the another protein of the MAPK/ERK pathway is selected from the group consisting of a RAF-inhibitor, an ERK-inhibitor, and/or a MEK- inhibitor.
  • the p90RSK-inhibitor is Bl- D1870
  • the RAF-inhibitor is selected from the group consisting of PLX4720
  • the ERK-inhibitor is selected from the group consisting of SCH772984 and VTX-11 e, and/or the MEK-inhibitor is selected from the group consisting of GSK1120212 (Trametinib) and MEK162.
  • a p90RSK-inhibitor in the manufacture of a medicament for the treatment of a cancer selected from the group consisting of NRAS-, KRAS- and BRAF-mutated cancer, preferably NRAS- mutated cancer, wherein the treatment comprises the simultaneous, separate or sequential administration of the p90RSK-inhibitor and an inhibitor of another protein of the MAPK/ERK pathway.
  • a protein is another protein than p90RSK, in the manufacture of a medicament for the treatment of a cancer selected from the group consisting of NRAS-,
  • KRAS- and BRAF-mutated cancer preferably NRAS-mutated cancer
  • the treatment comprises the simultaneous, separate or sequential administration of a p90RSK-inhibitor and the inhibitor of the another protein of the MAPK/ERK pathway.
  • said inhibitor of another protein of the MAPK/ERK pathway is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-N-ERK pathway
  • the cancer is melanoma, preferably NRAS-mutated melanoma.
  • the p90RSK-inhibitor is BI-D1870
  • the RAF- inhibitor is selected from the group consisting of PLX4720 (Vemurafenib)
  • GSK21 18436 (Dabrafenib)
  • the ERK-inhibitor is selected from the group consisting of SCH772984 and VTX-11 e
  • the MEK-inhibitor is selected from the group consisting of GSK1120212 (Trametinib) and MEK162.
  • a method for the treatment of a cancer selected from the group consisting of NRAS-, KRAS- and BRAF-mutated cancer, preferably NRAS-mutated cancer, wherein the method comprises the simultaneous, separate or sequential administering to a patient of a p90RSK-inhibitor and an inhibitor of another protein of the MAPK/ERK pathway.
  • said inhibitor of another protein of the MAPK/ERK pathway is selected from the group consisting of a RAF- inhibitor, an ERK-inhibitor, and/or a MEK-inhibitor.
  • the cancer is melanoma, preferably NRAS-mutated melanoma.
  • the p90RSK-inhibitor is BI-D1870
  • the RAF-inhibitor is selected from the group consisting of PLX4720 (Vemurafenib), and GSK2118436 (Dabrafenib)
  • the ERK-inhibitor is selected from the group consisting of SCH772984 and VTX-11 e
  • the MEK- inhibitor is selected from the group consisting of GSK1120212 (Trametinib) and
  • the treatment of the patient includes treatment in the first line or second line, or third line.
  • the disclosure herein can advantageously be used in patients that, e.g. in monotherapy, show reduced response to the use of an MEK-inhibitor, a ERK- inhibitor, a RAF-inhibitor, either from the start, or after a certain period of treatment with the MEK-inhibitor, ERK-inhibitor, and/or RAF-inhibitor, for example patients that are resistant to such inhibitor.
  • BRaf inhibitor PLX4720 (Vemurafenib), GSK21 18436 (Dabrafenib)
  • MEK inhibitor GSK1120212 (Trametinib), MEK162
  • ERK inhibitor SCH772984, VTX-11 e
  • p90RSK inhibitor BI-D1870
  • Malignant melanoma is an example of a highly aggressive cancer with rising incidence worldwide and, once metastasized, is notoriously difficult to treat.
  • the most commonly mutated genes in cutaneous melanoma are BRAF and NRAS, whereas oncogenic KRAS is also observed in a minority of the cases.
  • Targeted therapies are now used for BRAF, but are lacking for NRAS.
  • MEK inhibitors show promise as future drugs for the treatment of NRAS mutant melanoma, but will probably be insufficient as single agents due to a limited response rate and toxicity issues.
  • NRAS and BRAF mutant melanoma patients develop resistance to MEK inhibitor MEK162 already after a median of 3.7 and 3.3 months, respectively (Ascierto et al. (2013), Lancet Oncol. 14, 249-256). It is known that intrinsic and acquired resistance to targeted agents can limit their therapeutic effect.
  • p90RSK2 As a hit in a panel of treatment-naive NRAS mutant melanoma cell lines with shRNAs and extended the validation to a larger panel of NRAS or BRAF mutant melanoma cell lines with a p90RSK inhibitor (BI-D1870), which inhibits all 4 isoforms equally.
  • p90RSK inhibition sensitizes melanoma cells to inhibitors targeting the MAPK/ERK pathway at different points in the signaling cascade (BRaf, MEK, or ERK).
  • these resistant sublines are able to survive and grow in the presence of MEK or ERK inhibitors. Since these ERK inhibitor resistant sublines show MAPK/ERK pathway reactivation to a level seen in their treatment-naive counterparts, it stands to reason that they remain dependent on the MAPK/ERK pathway. We found that the ERK inhibitor resistant melanoma sublines of NRAS mutant melanoma can be killed by a combination treatment of ERK or MEK inhibitor with p90RSK inhibitor, just like their treatment-naive counterparts.
  • targeting the MAPK/ERK pathway at multiple points in the signalling cascade is not only effective in, for example, treatment- naive NRAS and BRAF mutant melanoma cell lines, but also in MAPK/ERK pathway inhibitor resistant sublines of e.g. NRAS mutant melanoma.
  • Simultaneous inhibition of several components of a pathway instead of a single component can be beneficial, because it inhibits the pathway more effectively.
  • Clinical experience with BRaf V600E and MEK inhibitors has shown that almost complete pathway inhibition (i.e. reduction in ERK activity by about 90%) is required to achieve a therapeutic effect.
  • Inhibition of a single pathway component can even have paradoxical activation effects by relieving feedback inhibition of the same pathway via down- regulation of the activity of this component.
  • the therapeutic effect on the tumor and dose-limiting toxicities are intimately linked for MAPK/ERK pathway inhibitors.
  • Such side effects have prompted patients to stop treatment even though an effect on tumor growth was apparent (Ascierto et al. (2013), Lancet Oncol. 14, 249-256).
  • the combination treatments we propose could provide a therapeutic window: they would allow to lower the dose of the individual drugs in a fashion that will reduce side effects and retain therapeutic activity.
  • BLM BLM
  • SK-MEL-147 BRAF mutation: V600E (mel 93.03, A375).
  • NRAS mutations Q61 R (BLM, SK-MEL-147).
  • DMEM Dulbecco's modified Eagle's Medium
  • Antibodies used were: phospho-AKT (Ser473, #9271), p42/p44 (#9102), phospho-p42/p44 (Thr202/Tyr204, #9106), MEK (#4694), phospho-MEK (Ser217/221 , 41G9, #9154), PARP (#9542), RSK1/2/3 (p90) (#9355), phospho-S6RP (Ser235/236, #4856), phospho- S6RP (Ser240/244, #2215), and S6RP (#2217) (all from Cell Signaling), phospho-RSK1 (p90) (Thr359/Ser363, #04-419, Millipore), alpha-tubulin (DM 1A, Sigma), AKT1/2 (sc- 8312), (from Santa Cruz), p27 (610241 , BD Transduction Laboratories). Protein detection for Western blotting was performed by fluorescence detection with the Odyssey reader (LI-COR Biosciences).
  • Treatment-naive melanoma cell lines are sensitive to combinations of MEK or ERK inhibitors with p90RSK inhibitors
  • pan-p90RSK inhibitor BI-D1870 showed only modest activity as single agent in aforementioned viability assays, used at an IC 2 o concentration it sensitized the tested NRAS mutant melanoma lines to MEK or ERK inhibitors producing an effect greater than the effect of the individual drugs, in an additive to synergistic fashion in long-term proliferation assays ( Figure 1 and Figure 2).
  • Figure 3 We also observed an at effect of the combination of ERK inhibitor and p90RSK inhibitor greater than that of the individual drugs on the proliferation of BRAF mutant melanoma lines. Note that the individual inhibitor concentrations were titrated to have little effect on their own (e.g.

Abstract

La présente invention concerne des combinaisons et compositions pharmaceutiques utiles dans le traitement de certains types de cancers. L'invention concerne également un procédé de traitement de ces certains types de cancers. En particulier, l'invention concerne l'utilisation combinée d'un inhibiteur de p90RSK et d'un inhibiteur d'une autre protéine du passage MAPK/ERK dans le traitement d'un cancer caractérisé par la mutation des gènes KRAS, NRAS ou BRAF, en particulier dans un mélanome caractérisé par la mutation du gène NRAS.
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