YAP1 Drives Resistance to RAF/MEK Inhibition

Treatment responses to targeted RAF and MEK inhibitors are limited by primary resistance in patients with RAS mutations and primary or acquired resistance in patients with BRAF-mutant tumors. To identify additional molecular mechanisms of resistance to RAF/MEK inhibitors, Lin and colleagues performed an shRNA screen in human BRAF^V600E non–small cell lung cancer (NSCLC) cells treated with the BRAF inhibitor vemurafenib and identified YAP1, which encodes an effector of Hippo signaling, as the top candidate gene. Consistent with a role for YAP1 in regulating the response to RAF/MEK inhibition, YAP1 silencing increased the sensitivity of BRAF-mutant NSCLC, melanoma, colon cancer, and thyroid cancer cell lines to both vemurafenib and the MEK inhibitor trametinib and augmented the response to RAF/MEK inhibition in xenograft models. Furthermore, YAP1 suppression enhanced the efficacy of MEK inhibition in various cancer cells harboring RAS mutations, including NSCLC, melanoma, and pancreatic adenocarcinoma cell lines. Dual suppression of YAP1 and RAF–MEK signaling was synthetically lethal and resulted in the synergistic induction of apoptosis in BRAF- and RAS-mutant models. Mechanistically, YAP1 and RAF–MEK signaling inhibited apoptosis via parallel transcriptional regulation of apoptotic genes including BCL2L1, which encodes the anti-apoptotic factor BCL-XL. Overexpression of BCL-XL reversed the sensitization to RAF/MEK inhibition induced by YAP1 silencing, whereas BCL-XL inhibition augmented the efficacy of RAF/MEK inhibitors, implicating BCL-XL as a key effector by which YAP1 promotes resistance to RAF/MEK inhibition. Importantly, elevated YAP1 expression was associated with diminished response to RAF/MEK inhibitor therapy in patients with BRAF-mutant tumors, and increased YAP1 levels were detected in melanomas after progression on RAF/MEK inhibitors, suggesting that YAP1 may be a biomarker of RAF/MEK inhibitor response. These data identify a broad role for YAP1 in promoting primary and acquired resistance to RAF/MEK inhibitors and suggest that YAP1 suppression may improve the efficacy of these inhibitors in BRAF- and RAS-mutant cancers.

Lin L, Sabnis AJ, Chan E, Olivas V, Cade L, Pazarentzos E, et al. The Hippo effector YAP1 promotes resistance to RAF- and MEK-targeted cancer therapies. Nat Genet 2015 Feb 9 [Epub ahead of print].