Open AccessSystematic analysis of BRAF V 600E melanomas reveals a role for JNK /c‐Jun pathway in adaptive resistance to drug‐induced apoptosis
Author(s) -
FallahiSichani Mohammad,
Moerke Nathan J,
Niepel Mario,
Zhang Tinghu,
Gray Nathanael S,
Sorger Peter K
Publication year - 2015
Publication title -
molecular systems biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.523
H-Index - 148
ISSN - 1744-4292
DOI - 10.15252/msb.20145877
Subject(s) - vemurafenib , biology , melanoma , cancer research , signal transduction , kinase , population , microbiology and biotechnology , medicine , environmental health , metastatic melanoma
Drugs that inhibit RAF / MEK signaling, such as vemurafenib, elicit profound but often temporary anti‐tumor responses in patients with BRAF V 600E melanoma. Adaptive responses to RAF / MEK inhibition occur on a timescale of hours to days, involve homeostatic responses that reactivate MAP kinase signaling and compensatory mitogenic pathways, and attenuate the anti‐tumor effects of RAF / MEK inhibitors. We profile adaptive responses across a panel of melanoma cell lines using multiplex biochemical measurement, single‐cell assays, and statistical modeling and show that adaptation involves at least six signaling cascades that act to reduce drug potency ( IC 50 ) and maximal effect (i.e., E max ≪ 1). Among these cascades, we identify a role for JNK /c‐Jun signaling in vemurafenib adaptation and show that RAF and JNK inhibitors synergize in cell killing. This arises because JNK inhibition prevents a subset of cells in a cycling population from becoming quiescent upon vemurafenib treatment, thereby reducing drug E max . Our findings demonstrate the breadth and diversity of adaptive responses to RAF / MEK inhibition and a means to identify which steps in a signaling cascade are most predictive of phenotypic response.