The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies

Abstract

Resistance to RAF- and MEK-targeted therapy is a major clinical challenge1–4. RAF and MEK inhibitors are initially but only transiently effective in some but not all patients with BRAF gene mutation and are largely ineffective in those with RAS gene mutation because of resistance5–14. Through a genetic screen in BRAF-mutant tumor cells, we show that the Hippo pathway effector YAP (encoded by YAP1) acts as a parallel survival input to promote resistance to RAF and MEK inhibitor therapy. Combined YAP and RAF or MEK inhibition was synthetically lethal not only in several BRAF-mutant tumor types but also in RAS-mutant tumors. Increased YAP in tumors harboring BRAF V600E was a biomarker of worse initial response to RAF and MEK inhibition in patients, establishing the clinical relevance of our findings. Our data identify YAP as a new mechanism of resistance to RAF- and MEK-targeted therapy. The findings unveil the synthetic lethality of combined suppression of YAP and RAF or MEK as a promising strategy to enhance treatment response and patient survival.

Targeted agents and immunotherapies: optimizing outcomes in melanoma

“…In some tumours, BRAF and MEK inhibition has been observed to increase signalling through the YAP pathway 127 , leading to escape from cell death via increased expression of the antiapoptotic protein Bcl-xL 128 (FIG. 4a).…”

The Hippo effector YAP regulates the response of cancer cells to MAPK pathway inhibitors

“…4,5 Resistance to RAF-MEK targeted therapy is a major clinical challenge. RAF-MEK inhibitors are initially, but only transiently, effective in some, but not all, patients with BRAF-mutant disease, and largely ineffective in patients with RASmutant disease because of resistance.…”

“…6 We used a pooled small hairpin RNA screen in human BRAF V600E mutant lung cancer cells to identify genes that when silenced enhanced the response to the approved BRAF inhibitor vemurafenib. 4 Through this genetic screen, we found that the Hippo pathway effector yes-associated protein 1 (YAP1) acts as a parallel survival input to promote resistance to RAF-MEK inhibitor therapy ( Fig. 1).…”

Report from the II Melanoma Translational Meeting of the Spanish Melanoma Group (GEM)

“…Secondly, activation of YAP1, already described by Dr. Rosell's group as a factor involved in resistance to targeted drugs (10,11), leads to the acquisition of an immunoresistant phenotype by promoting the expression of immunosuppressive molecules EOMES and PD-1 (12), as well as the secretion of the chemokine CXCL5, leading to increased tumor infiltration by immunosuppressive cells, called myeloid derived suppressor cells (MDSCs) (13).…”