Systematic analysis of BRAFV600E melanomas reveals a role for JNK/c‐Jun pathway in adaptive resistance to drug‐induced apoptosis

Molecular Systems Biology

Mohammad Fallahi-Sichani¹  Nathan J Moerke¹  Mario Niepel¹  Tinghu Zhang²  Nathanael S Gray² 

[1]HMS LINCS Center, Department of Systems Biology, Harvard Medical School, Boston, MA, USA

[2]Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

关键词: adaptive responses;    BRAFV600E melanomas;    cell‐to‐cell variability;    RAF and MEK inhibitors;    submaximal drug effect;   

DOI  :  10.15252/msb.20145877

来源: Wiley

【 摘 要 】

Abstract

Drugs that inhibit RAF/MEK signaling, such as vemurafenib, elicit profound but often temporary anti-tumor responses in patients with BRAF^V600E 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 (IC₅₀) 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.

Synopsis

Adaptive responses to RAF/MEK inhibitors are analyzed systematically across a panel of BRAF^V600E melanoma lines to reveal a role for cell-to-cell variability induced by the JNK/c-Jun pathway and other factors in adaptive drug resistance.

• Adaptive responses are profiled using a combination of multiplex measurements across time, dose, cell line and drug type, statistical modeling and single-cell analysis.
• BRAF^V600E melanoma lines differ in sensitivity to RAF/MEK inhibition with respect to both IC₅₀ and maximal effect (E_max), reflecting cell-to-cell variability in drug response.
• Adaptive responses to RAF/MEK inhibition are diverse and involve multiple signaling pathways.
• The JNK/c-Jun pathway is a common adaptive response that decreases drug maximum effect.
• JNK inhibition prevents induction of quiescence by RAF inhibition and promotes apoptosis.

【 授权许可】

CC BY   
© 2015 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.