Progression of RAS-mutant leukemia during RAF inhibitor treatment.

Vemurafenib, a selective RAF inhibitor, extends survival among patients with BRAF V600E-mutant melanoma. Vemurafenib inhibits ERK signaling in BRAF V600E-mutant cells but activates ERK signaling in BRAF wild-type cells. This paradoxical activation of ERK signaling is the mechanistic basis for the development of RAS-mutant squamous-cell skin cancers in patients treated with RAF inhibitors. We report the accelerated growth of a previously unsuspected RAS-mutant leukemia in a patient with melanoma who was receiving vemurafenib. Exposure to vemurafenib induced hyperactivation of ERK signaling and proliferation of the leukemic cell population, an effect that was reversed on drug withdrawal.

[1]  J. Wisell,et al.  Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma , 2013 .

[2]  K. Flaherty,et al.  Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. , 2012, The New England journal of medicine.

[3]  A. Hauschild,et al.  Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial , 2012, The Lancet.

[4]  A. Hauschild,et al.  Atypical melanocytic proliferations and new primary melanomas in patients with advanced melanoma undergoing selective BRAF inhibition. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  Dirk Schadendorf,et al.  Improved survival with MEK Inhibition in BRAF-mutated melanoma for the METRIC Study Group , 2012 .

[6]  J. Wolchok,et al.  The immunological impact of the RAF inhibitor BMS908662: Preclinical and early clinical experience in combination with CTLA-4 blockade. , 2012 .

[7]  Lauren E Haydu,et al.  Distinguishing Clinicopathologic Features of Patients with V600E and V600K BRAF-Mutant Metastatic Melanoma , 2012, Clinical Cancer Research.

[8]  Yu Shyr,et al.  Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. , 2012, The New England journal of medicine.

[9]  J. Maciejewski,et al.  Chronic myelomonocytic leukemia and atypical chronic myeloid leukemia: novel pathogenetic lesions. , 2012, Seminars in oncology.

[10]  K. Flaherty,et al.  RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. , 2012, The New England journal of medicine.

[11]  T. Eberlein,et al.  Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation , 2012 .

[12]  R. Arceci.  RAS Mutations Are Associated With the Development of Cutaneous Squamous Cell Tumors in Patients Treated With RAF Inhibitors , 2012 .

[13]  S. Heidorn,et al.  Nilotinib and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug-resistant chronic myeloid leukemia. , 2011, Cancer cell.

[14]  C. Robert,et al.  RAF inhibition and induction of cutaneous squamous cell carcinoma , 2011, Current opinion in oncology.

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

[16]  B. Taylor,et al.  The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner , 2010, Proceedings of the National Academy of Sciences.

[17]  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.

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

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

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

[21]  Kam Y. J. Zhang,et al.  Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity , 2008, Proceedings of the National Academy of Sciences.

[22]  D. Barford,et al.  Mechanism of Activation of the RAF-ERK Signaling Pathway by Oncogenic Mutations of B-RAF , 2004, Cell.

[23]  D. Polsky,et al.  Analysis of BRAF and N-RAS mutations in metastatic melanoma tissues. , 2003, Cancer research.

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

[25]  Philip R. Cohen,et al.  Paradoxical activation of Raf by a novel Raf inhibitor. , 1999, Chemistry & biology.

[26]  H. Kantarjian,et al.  RAS mutations are rare events in Philadelphia chromosome-negative/bcr gene rearrangement-negative chronic myelogenous leukemia, but are prevalent in chronic myelomonocytic leukemia , 1990 .

[27]  H. Kantarjian,et al.  RAS mutations are rare events in Philadelphia chromosome-negative/bcr gene rearrangement-negative chronic myelogenous leukemia, but are prevalent in chronic myelomonocytic leukemia. , 1990, Blood.