Data from MAP Kinase Pathway Alterations in <i>BRAF</i>-Mutant Melanoma Patients with Acquired Resistance to Combined RAF/MEK Inhibition

Abstract

<div>Abstract<p>Treatment of <i>BRAF</i>-mutant melanoma with combined dabrafenib and trametinib, which target RAF and the downstream MAP–ERK kinase (MEK)1 and MEK2 kinases, respectively, improves progression-free survival and response rates compared with dabrafenib monotherapy. Mechanisms of clinical resistance to combined RAF/MEK inhibition are unknown. We performed whole-exome sequencing (WES) and whole-transcriptome sequencing (RNA-seq) on pretreatment and drug-resistant tumors from five patients with acquired resistance to dabrafenib/trametinib. In three of these patients, we identified additional mitogen-activated protein kinase (MAPK) pathway alterations in the resistant tumor that were not detected in the pretreatment tumor, including a novel activating mutation in MEK2 (<i>MEK2</i><sup>Q60P</sup>). <i>MEK2</i><sup>Q60P</sup> conferred resistance to combined RAF/MEK inhibition <i>in vitro</i>, but remained sensitive to inhibition of the downstream kinase extracellular signal–regulated kinase (ERK). The continued MAPK signaling-based resistance identified in these patients suggests that alternative dosing of current agents, more potent RAF/MEK inhibitors, and/or inhibition of the downstream kinase ERK may be needed for durable control of <i>BRAF</i>-mutant melanoma.</p><p><b>Significance:</b> This study represents an initial clinical genomic study of acquired resistance to combined RAF/MEK inhibition in <i>BRAF</i>-mutant melanoma, using WES and RNA-seq. The presence of diverse resistance mechanisms suggests that serial biopsies and genomic/molecular profiling at the time of resistance may ultimately improve the care of patients with resistant <i>BRAF</i>-mutant melanoma by specifying tailored targeted combinations to overcome specific resistance mechanisms. <i>Cancer Discov; 4(1); 61–8. ©2013 AACR</i>.</p><p>See related commentary by Solit and Rosen, p. 27</p><p>This article is highlighted in the In This Issue feature, p. 1</p></div>