XLSX file 13K, Supplementary Table S5. PI3K pathway alterations. This table provides additional details on the PI3K pathway alterations observed in this cohort. Additional information regarding the time point, protein change, and appropriate reference are provided. Biopsy time point entries in gray denote situations where the tumor was unavailable for sequencing. Allelic fractions in bold denote situations where there is evidence for loss of the alternate allele between time points. (PMID = PubMed identification number). For activating or inactivating alterations, predicted function was derived by review of the published literature. The "likely" designation was reserved for alterations that occurred at the same amino acid residue as reported events but involved different changes at that site. For remaining missense mutations, "Probably Damaging" and "Possibly Damaging" designations were obtained from PolyPhen2 in silico predictions; alterations that met that criteria had PolyPhen2 scores between 0.9 and 1. Remaining nonsense mutations were considered "Probably Damaging"
ARTICLE ABSTRACT
Most patients with BRAFV600-mutant metastatic melanoma develop resistance to selective RAF kinase inhibitors. The spectrum of clinical genetic resistance mechanisms to RAF inhibitors and options for salvage therapy are incompletely understood. We performed whole-exome sequencing on formalin-fixed, paraffin-embedded tumors from 45 patients with BRAFV600-mutant metastatic melanoma who received vemurafenib or dabrafenib monotherapy. Genetic alterations in known or putative RAF inhibitor resistance genes were observed in 23 of 45 patients (51%). Besides previously characterized alterations, we discovered a “long tail” of new mitogen-activated protein kinase (MAPK) pathway alterations (MAP2K2, MITF) that confer RAF inhibitor resistance. In three cases, multiple resistance gene alterations were observed within the same tumor biopsy. Overall, RAF inhibitor therapy leads to diverse clinical genetic resistance mechanisms, mostly involving MAPK pathway reactivation. Novel therapeutic combinations may be needed to achieve durable clinical control of BRAFV600-mutant melanoma. Integrating clinical genomics with preclinical screens may model subsequent resistance studies.Significance: The use of RAF inhibitors for BRAFV600-mutant metastatic melanoma improves patient outcomes, but most patients demonstrate early or acquired resistance to this targeted therapy. We reveal the genetic landscape of clinical resistance mechanisms to RAF inhibitors from patients using whole-exome sequencing, and experimentally assess new observed mechanisms to define potential subsequent treatment strategies. Cancer Discov; 4(1); 94–109. ©2013 AACR.See related commentary by Solit and Rosen, p. 27This article is highlighted in the In This Issue feature, p. 1
