Resistance to BRAF inhibitors: unraveling mechanisms and future treatment options.

The mitogen-activated protein kinase (MAPK) pathway has emerged as a central target for melanoma therapy due to its persistent activation in the majority of tumors. Several BRAF inhibitors aimed at curbing MAPK pathway activity are currently in advanced stages of clinical investigation. However, their therapeutic success is limited by the emergence of drug resistance, as responses are transient and tumors eventually recur. To develop effective and long-lasting therapies for melanoma patients, it is essential to understand the mechanisms underlying resistance to BRAF inhibitors. Here, we briefly review recent preclinical studies that have provided insight into the molecular mechanisms of resistance to BRAF inhibitors and discuss potential strategies to treat drug-resistant melanomas.

[1]  Chao Zhang,et al.  RAF inhibitors transactivate RAF dimers and ERK signaling in cells with wild-type BRAF , 2010, Nature.

[2]  D. Heimbrook,et al.  RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. , 2010, Cancer research.

[3]  A. Hauschild,et al.  Improved survival with vemurafenib in melanoma with BRAF V600E mutation. , 2011, The New England journal of medicine.

[4]  Adrian V. Lee,et al.  The type I insulin-like growth factor receptor pathway: a key player in cancer therapeutic resistance. , 2008, Frontiers in bioscience : a journal and virtual library.

[5]  M. Belvin,et al.  RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth , 2010, Nature.

[6]  L. Schuchter,et al.  Metastatic melanoma , 2001, Current treatment options in oncology.

[7]  S. Ariyan,et al.  Incidence of the V600K mutation among melanoma patients with BRAF mutations, and potential therapeutic response to the specific BRAF inhibitor PLX4032 , 2010, Journal of Translational Medicine.

[8]  M. Herlyn,et al.  PLX4032, a potent inhibitor of the B‐Raf V600E oncogene, selectively inhibits V600E‐positive melanomas , 2010, Pigment cell & melanoma research.

[9]  Hieu T. Do,et al.  Demonstration of a genetic therapeutic index for tumors expressing oncogenic BRAF by the kinase inhibitor SB-590885. , 2006, Cancer research.

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

[11]  S. Nelson,et al.  Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation , 2010, Nature.

[12]  Nikhil Wagle,et al.  Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  A. Aplin,et al.  Akt3-mediated resistance to apoptosis in B-RAF-targeted melanoma cells. , 2010, Cancer research.

[14]  J. Reis-Filho,et al.  Kinase-Dead BRAF and Oncogenic RAS Cooperate to Drive Tumor Progression through CRAF , 2010, Cell.

[15]  J. O'Brien,et al.  Mutations in GNA11 in uveal melanoma. , 2010, The New England journal of medicine.

[16]  K. O'Byrne,et al.  Receptor tyrosine kinases and their activation in melanoma , 2011, Pigment cell & melanoma research.

[17]  K. Flaherty,et al.  Inhibition of mutated, activated BRAF in metastatic melanoma. , 2010, The New England journal of medicine.

[18]  Kam Y. J. Zhang,et al.  Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma , 2010, Nature.

[19]  Jonathan Chernoff,et al.  Faculty Opinions recommendation of COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. , 2011 .

[20]  Damien Kee,et al.  Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. , 2010, Cancer cell.

[21]  M. Herlyn,et al.  Targeting BRAF in Advanced Melanoma: A First Step toward Manageable Disease , 2011, Clinical Cancer Research.

[22]  A. Aplin,et al.  Hyperactivation of MEK–ERK1/2 signaling and resistance to apoptosis induced by the oncogenic B-RAF inhibitor, PLX4720, in mutant N-RAS melanoma cells , 2011, Oncogene.