Showing papers by "Mark M. Kockx published in 2012"
Hoffmann-La Roche1, Autonomous University of Barcelona2, Plexxikon3, University of California, Los Angeles4, Harvard University5, Memorial Sloan Kettering Cancer Center6, Peter MacCallum Cancer Centre7, Medical College of Wisconsin8, University of Colorado Denver9, Baylor University Medical Center10, Vanderbilt University11
TL;DR: In this article, the authors performed a molecular analysis to identify oncogenic mutations (HRAS, KRAS, NRAS, CDKN2A, and TP53) in the lesions from patients treated with the BRAF inhibitor vemurafenib.
Abstract: Background Cutaneous squamous-cell carcinomas and keratoacanthomas are common findings in patients treated with BRAF inhibitors. Methods We performed a molecular analysis to identify oncogenic mutations (HRAS, KRAS, NRAS, CDKN2A, and TP53) in the lesions from patients treated with the BRAF inhibitor vemurafenib. An analysis of an independent validation set and functional studies with BRAF inhibitors in the presence of the prevalent RAS mutation was also performed. Results Among 21 tumor samples, 13 had RAS mutations (12 in HRAS). In a validation set of 14 samples, 8 had RAS mutations (4 in HRAS). Thus, 60% (21 of 35) of the specimens harbored RAS mutations, the most prevalent being HRAS Q61L. Increased proliferation of HRAS Q61L–mutant cell lines exposed to vemurafenib was associated with mitogen-activated protein kinase (MAPK)–pathway signaling and activation of ERK-mediated transcription. In a mouse model of HRAS Q61L–mediated skin carcinogenesis, the vemurafenib analogue PLX4720 was not an initiator or...
937 citations
Vanderbilt University1, New York University2, University of Pennsylvania3, University of Colorado Boulder4, Peter MacCallum Cancer Centre5, Baylor University6, University of Pittsburgh7, Harvard University8, University of Texas MD Anderson Cancer Center9, University of Newcastle10, Royal Prince Alfred Hospital11, Hoffmann-La Roche12, Plexxikon13, University of California, Los Angeles14
TL;DR: A centralized analysis of pretreatment, cycle 1, day 15 (D15), and progression (DP) tumor samples collected during the phase II BRIM-2 trial showed high levels of ERK phosphorylation were seen at BL indicating constitutive MAPK signaling due to the BRAF mutation.
Abstract: 8503^ Background: Vem induces frequent clinical responses (RR >50%) and improved survival in patients (pts) with BRAF-mutated metastatic melanoma. Multiple mechanisms of escape from vem have been p...
27 citations