Systematic analysis of BRAFV600E melanomas reveals a role for JNK/c-Jun pathway in adaptive resistance to drug-induced apoptosis |
| |
| Authors: | Mohammad Fallahi-Sichani Nathan J Moerke Mario Niepel Tinghu Zhang Nathanael S Gray Peter K Sorger |
| |
| Affiliation: | 1HMS LINCS Center, Department of Systems Biology, Harvard Medical School, Boston, MA, USA;2Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA;3Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA |
| |
| Abstract: | Drugs that inhibit RAF/MEK signaling, such as vemurafenib, elicit profound but often temporary anti-tumor responses in patients with BRAFV600E 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., Emax ≪ 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 Emax. 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. |
| |
| Keywords: | adaptive responses BRAFV600E melanomas cell-to-cell variability RAF and MEK inhibitors submaximal drug effect |
|
|
