Oncogene Mimicry as a Mechanism of Primary Resistance to BRAF Inhibitors

•BRAF dependency is uncoupled from MAPK inhibitor efficacy•RAS/RAF/MEK complex formation buffers pathway inhibition in primary resistant cells•Autocrine secretion of IL-6 contributes to primary resistance signaling•Oncogene mimicry is a strategy of primary resistance to BRAF inhibition

SummaryDespite the development of potent RAF/mitogen-activated protein kinase (MAPK) pathway inhibitors, only a fraction of BRAF-mutant patients benefit from treatment with these drugs. Using a combined chemogenomics and chemoproteomics approach, we identify drug-induced RAS-RAF-MEK complex formation in a subset of BRAF-mutant cancer cells characterized by primary resistance to vemurafenib. In these cells, autocrine interleukin-6 (IL-6) secretion may contribute to the primary resistance phenotype via induction of JAK/STAT3 and MAPK signaling. In a subset of cell lines, combined IL-6/MAPK inhibition is able to overcome primary resistance to BRAF-targeted therapy. Overall, we show that the signaling plasticity exerted by primary resistant BRAF-mutant cells is achieved by their ability to mimic signaling features of oncogenic RAS, a strategy that we term “oncogene mimicry.” This model may guide future strategies for overcoming primary resistance observed in these tumors.

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