The MAPK pathway in melanoma

Purpose of review As understanding of molecular and genetic processes in cancer evolves, so does appreciation of tumor heterogeneity. Tumor profiling has expanded knowledge of relevant pathways, and their interplay. Similar to the revolution in breast cancer with the discovery and successful therapeutic targeting of HER2/neu, the melanoma field is rapidly evolving. The MAPK pathway is dysregulated in most melanomas. Several therapeutic agents directed against this pathway are in development. This review summarizes current understanding of the MAPK pathway in melanoma biology and therapeutic strategies. Recent findings Recent data support the concept of distinct groups of molecular and genetic abnormalities in melanomas, related to type of sun exposure and body site. MAPK abnormalities, specifically BRAF or NRAS mutations, are most prevalent. The efficacy of sorafenib, a multitargeted kinase inhibitor, in melanoma is still under evaluation. While ineffective as a single agent, efficacy in combination with chemotherapy or targeted agents is being assessed. More specific inhibitors of BRAF, or other MAPK members, may prove more effective. Summary Tumor profiling has led to exciting advances. The MAPK pathway is one of several potentially targetable pathways in melanoma. Ultimately, combinatorial therapeutics against relevant disrupted pathways in specific tumors likely will prove most successful.

[1]  A. Hauschild,et al.  Randomized phase III study of paclitaxel plus carboplatin with or without sorafenib as second-line treatment in patients with advanced melanoma , 2007 .

[2]  L. Fecher,et al.  Toward a molecular classification of melanoma. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  M. Herlyn,et al.  Mutant V600E BRAF Increases Hypoxia Inducible Factor-1α Expression in Melanoma , 2007 .

[4]  Vivienne Marsh,et al.  Biological Characterization of ARRY-142886 (AZD6244), a Potent, Highly Selective Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor , 2007, Clinical Cancer Research.

[5]  R. Marais,et al.  Melanoma biology and new targeted therapy , 2007, Nature.

[6]  V. Sondak,et al.  Chemotherapy for metastatic melanoma , 2007, Cancer.

[7]  Apurva A Desai,et al.  Sorafenib in advanced clear-cell renal-cell carcinoma. , 2007, The New England journal of medicine.

[8]  D. Pinkel,et al.  Somatic activation of KIT in distinct subtypes of melanoma. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  M. Ratain,et al.  Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis , 2006, British Journal of Cancer.

[10]  D. Krahl,et al.  The oncogenic B-raf V599E mutation occurs more frequently in melanomas at sun-protected body sites. , 2006, International journal of oncology.

[11]  K. Flaherty,et al.  Updated results of a randomized phase II study comparing two schedules of temozolomide in combination with sorafenib in patients with advanced melanoma , 2006 .

[12]  S. Ramurthy,et al.  CHIR-265 is a potent selective inhibitor of c-Raf/B-Raf/mutB-Raf that effectively inhibits proliferation and survival of cancer cell lines with Ras/Raf pathway mutations , 2006 .

[13]  K. Flaherty.  Chemotherapy and Targeted Therapy Combinations in Advanced Melanoma , 2006, Clinical Cancer Research.

[14]  M. Atkins,et al.  Targeting the Mitogen-Activated Protein Kinase Pathway in the Treatment of Malignant Melanoma , 2006, Clinical Cancer Research.

[15]  Pablo Rodriguez-Viciana,et al.  Germline Mutations in Genes Within the MAPK Pathway Cause Cardio-facio-cutaneous Syndrome , 2006, Science.

[16]  Tak W. Mak,et al.  Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis , 2006, Nature Reviews Cancer.

[17]  R. Hennekam,et al.  Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome , 2006, Nature Genetics.

[18]  Todd R. Golub,et al.  BRAF mutation predicts sensitivity to MEK inhibition , 2006, Nature.

[19]  N. Rosen,et al.  V600E B-Raf requires the Hsp90 chaperone for stability and is degraded in response to Hsp90 inhibitors. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[20]  J. Pouysségur,et al.  Targeting the ERK signaling pathway in cancer therapy , 2006, Annals of medicine.

[21]  P. Workman,et al.  Activated B-RAF is an Hsp90 client protein that is targeted by the anticancer drug 17-allylamino-17-demethoxygeldanamycin. , 2005, Cancer research.

[22]  Yiling Lu,et al.  Exploiting the PI3K/AKT Pathway for Cancer Drug Discovery , 2005, Nature Reviews Drug Discovery.

[23]  J. Fridlyand,et al.  Distinct sets of genetic alterations in melanoma. , 2005, The New England journal of medicine.

[24]  M. Beeram,et al.  Raf: a strategic target for therapeutic development against cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  Yukichi Tanaka,et al.  Germline mutations in HRAS proto-oncogene cause Costello syndrome , 2005, Nature Genetics.

[26]  W. Reardon,et al.  Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases , 2005, Journal of Medical Genetics.

[27]  P. LoRusso,et al.  Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  P. Khavari,et al.  Use of human tissue to assess the oncogenic activity of melanoma-associated mutations , 2005, Nature Genetics.

[29]  S. Leung,et al.  BRAF and NRAS mutations are uncommon in melanomas arising in diverse internal organs , 2005, Journal of Clinical Pathology.

[30]  D. Hedley,et al.  Raf kinase as a target for anticancer therapeutics , 2005, Molecular Cancer Therapeutics.

[31]  K. Giehl.  Oncogenic Ras in tumour progression and metastasis , 2005, Biological chemistry.

[32]  P Kelly Marcom,et al.  Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  J. Hecht,et al.  Multicenter phase II study of the oral MEK inhibitor, CI-1040, in patients with advanced non-small-cell lung, breast, colon, and pancreatic cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  J. Warmus,et al.  Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition , 2004, Nature Structural &Molecular Biology.

[35]  D. Auclair,et al.  BAY 43-9006 Exhibits Broad Spectrum Oral Antitumor Activity and Targets the RAF/MEK/ERK Pathway and Receptor Tyrosine Kinases Involved in Tumor Progression and Angiogenesis , 2004, Cancer Research.

[36]  K. Flaherty,et al.  Phase I/II trial of BAY 43-9006, carboplatin (C) and paclitaxel (P) demonstrates preliminary antitumor activity in the expansion cohort of patients with metastatic melanoma. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[37]  D. Sidransky,et al.  Exon 15 BRAF Mutations Are Uncommon in Melanomas Arising in Nonsun-Exposed Sites , 2004, Clinical Cancer Research.

[38]  B. Weber,et al.  Absence of BRAF mutations in UV-protected mucosal melanomas , 2004, Journal of Medical Genetics.

[39]  P. M. Campbell,et al.  Oncogenic Ras and its role in tumor cell invasion and metastasis. , 2004, Seminars in cancer biology.

[40]  C. Springer,et al.  V599EB-RAF is an Oncogene in Melanocytes , 2004, Cancer Research.

[41]  M. Vieth,et al.  Mutations of BRAF and KRAS2 in the development of Barrett's adenocarcinoma , 2004, Oncogene.

[42]  Ajay N. Jain,et al.  Determinants of BRAF mutations in primary melanomas. , 2003, Journal of the National Cancer Institute.

[43]  H. S. Kim,et al.  BRAF mutations in non-Hodgkin's lymphoma , 2003, British Journal of Cancer.

[44]  M. Nikiforova,et al.  BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. , 2003, The Journal of clinical endocrinology and metabolism.

[45]  Suk Woo Nam,et al.  BRAF and KRAS mutations in stomach cancer , 2003, Oncogene.

[46]  F. Sommerer,et al.  Mutations of the BRAF gene in squamous cell carcinoma of the head and neck , 2003, Oncogene.

[47]  J. Reis-Filho,et al.  Expression of c-met Tyrosine Kinase Receptor Is Biologically and Prognostically Relevant for Primary Cutaneous Malignant Melanomas , 2003, Oncology.

[48]  David E Fisher,et al.  Microphthalamia-associated transcription factor: a critical regulator of pigment cell development and survival , 2003, Oncogene.

[49]  F. Haluska,et al.  PTEN signaling pathways in melanoma , 2003, Oncogene.

[50]  K. Smalley,et al.  A pivotal role for ERK in the oncogenic behaviour of malignant melanoma? , 2003, International journal of cancer.

[51]  F. Sommerer,et al.  Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma , 2003, Gut.

[52]  P. Ladenson,et al.  BRAF mutation in papillary thyroid carcinoma. , 2003, Journal of the National Cancer Institute.

[53]  Yuri E Nikiforov,et al.  High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. , 2003, Cancer research.

[54]  I. Shih,et al.  Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. , 2003, Journal of the National Cancer Institute.

[55]  R. MacKie,et al.  Absence of exon 15 BRAF germline mutations in familial melanoma , 2003, Human mutation.

[56]  Richard Wooster,et al.  BRAF and RAS mutations in human lung cancer and melanoma. , 2002, Cancer research.

[57]  M. Meyerson,et al.  Missense mutations of the BRAF gene in human lung adenocarcinoma. , 2002, Cancer research.

[58]  J. Arbiser,et al.  Mitogen-actived protein kinase activation is an early event in melanoma progression. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[59]  M. Stratton,et al.  Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia. , 2002, Cancer research.

[60]  K. Kinzler,et al.  Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status , 2002, Nature.

[61]  A. Nicholson,et al.  Mutations of the BRAF gene in human cancer , 2002, Nature.

[62]  G. Merlino,et al.  Hepatocyte growth factor/scatter factor activates proliferation in melanoma cells through p38 MAPK, ATF-2 and cyclin D1 , 2002, Oncogene.

[63]  P. Workman,et al.  HSP90 as a new therapeutic target for cancer therapy: the story unfolds , 2002, Expert opinion on biological therapy.

[64]  P. Heinrich,et al.  Mitogen-activated protein kinases control p27/Kip1 expression and growth of human melanoma cells. , 2001, The Biochemical journal.

[65]  A. Alessandrini,et al.  MEK1 activation rescues Jurkat T cells from Fas-induced apoptosis. , 1999, Cellular immunology.

[66]  L. Chin,et al.  Cooperative effects of INK4a and ras in melanoma susceptibility in vivo. , 1997, Genes & development.

[67]  J. Hoeffler,et al.  Ras mutations in human melanoma: a marker of malignant progression. , 1994, The Journal of investigative dermatology.

[68]  Joyce Bos.  ras oncogenes in human cancer: a review. , 1989, Cancer research.

[69]  L. J. Veer,et al.  N-ras mutations in human cutaneous melanoma from sun-exposed body sites , 1989, Molecular and cellular biology.

[70]  J. Opitz,et al.  New multiple congenital anomalies/mental retardation syndrome with cardio-facio-cutaneous involvement--the CFC syndrome. , 1986, American journal of medical genetics.

[71]  D. Pinkel,et al.  Congenital melanocytic nevi frequently harbor NRAS mutations but no BRAF mutations. , 2007, The Journal of investigative dermatology.

[72]  A. Jemal,et al.  Cancer Statistics, 2007 , 2007, CA: a cancer journal for clinicians.

[73]  S. Wilhelm,et al.  Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. , 2006, Methods in enzymology.

[74]  K. Flaherty,et al.  Preliminary results of a randomized phase II study comparing two schedules of temozolomide in combination with sorafenib in patients with advanced melanoma. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[75]  N. Rosen,et al.  B-Raf requires the Hsp 90 chaperone for stability and is degraded in response to Hsp 90 inhibitors , 2005 .

[76]  M. Teitell,et al.  Mutations in Costello Syndrome : Detection of Constitutional Activating Mutations in Codon 12 and 13 and Loss of Wild-Type Allele in Malignancy , 2005 .

[77]  S. Colla,et al.  Downmodulation of ERK protein kinase activity inhibits VEGF secretion by human myeloma cells and myeloma-induced angiogenesis , 2004, Leukemia.

[78]  S. H. Lee,et al.  BRAF mutations in acute leukemias , 2004, Leukemia.

[79]  P. Meltzer,et al.  High frequency of BRAF mutations in nevi , 2003, Nature Genetics.

[80]  D. Schadendorf,et al.  Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[81]  S. van der Flier,et al.  Analysis of N-ras mutations in human cutaneous melanoma: tumor heterogeneity detected by polymerase chain reaction/single-stranded conformation polymorphism analysis. , 1995, Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer.

[82]  C. Cordon-Cardo,et al.  Analysis of ras oncogenes in malignant melanoma and precursor lesions: correlation of point mutations with differentiation phenotype. , 1989, Oncogene.

[83]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.