Actin Remodeling Confers BRAF Inhibitor Resistance to Melanoma Cells through YAP/TAZ Activation
The emergence of acquired resistance to targeted anti-cancer agents poses a critical hurdle for improving cancer patient prognosis. We found that BRAF V600E mutant melanoma cells undergo active actin cytoskeletal remodeling in response to the BRAF inhibitor PLX4032, and the remodeling promotes nuclear localization of YAP/TAZ oncoproteins, conferring adaptive resistance to PLX4032.
The activation of transcriptional coactivators YAP and its paralog TAZ has been shown to promote resistance to anti-cancer therapies. YAP/TAZ activity is tightly coupled to actin cytoskeleton architecture. However, the influence of actin remodeling on cancer drug resistance remains largely unexplored. We report a pivotal role of actin remodeling in YAP/TAZ-dependent BRAF inhibitor resistance in BRAF V600E mutant melanoma cells. Melanoma cells resistant to BRAF inhibitor PLX4032 exhibit an increase in actin stress fiber formation, which appears to promote the nuclear accumulation of YAP/TAZ. Knockdown of YAP/TAZ overcomes PLX4032 resistance, whereas overexpression of constitutively active YAP induces resistance. Moreover, inhibition of actin polymerization and cytoskeletal tension in melanoma cells suppresses both YAP/TAZ activation and PLX4032 resistance. Our siRNA library screening identifies actin dynamics regulator TESK1 as a novel vulnerable point of the YAP/TAZ-dependent resistance pathway. These results suggest that inhibition of actin remodeling is a promising synthetic lethal strategy to suppress resistance in BRAF inhibitor therapies.
EMBO Journal 2016, 35:462-478 (http://emboj.embopress.org/content/35/5/462.long)
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