Role of YAP/TAZ in resistance to anti-cancer therapy in melanoma cells

Abstract

Previous studies have demonstrated that the activation of Hippo pathway effectors, YAP and its paralog TAZ, contributes to multiple malignant processes. BRAF inhibitor (BRAFi) treatment decreases tumor burdens in BRAF V600 mutant melanoma patients. However, the emergence of drug resistance limits its therapeutic efficacy. Here I first demonstrate that actin cytoskeleton remodeling plays a pivotal role in BRAFi resistance development through YAP/TAZ activation in melanoma cells. Vemurafenib-resistant melanoma cells exhibits a substantial increase in actin stress fiber formation compared to parental cells, which promotes nuclear accumulation and activation of YAP/TAZ. YAP/TAZ depletion restores vemurafenib sensitivity in resistant cells, whereas overexpression of constitutively active YAP (YAP-5SA) raises resistance to vemurafenib. Moreover, inhibition of actin polymerization reduces YAP/TAZ activity and suppresses cell viability in resistant cells. From a kinome siRNA library screening, I identified TESK1, an actin dynamics regulator, as a candidate target for BRAFi resistance. TESK1 knockdown decreases both actin stress fiber formation and YAP/TAZ nuclear translocation, provoking growth arrest of resistant melanoma cells. These results suggest that inhibition of actin remodeling is a candidate strategy to suppress YAP/TAZ-driven resistance in BRAFi therapies. Secondly, I found that BRAFi-resistant melanoma cells induce PD-1/PD-L1-mediated suppression of CD8+ T cells by activation of YAP. PD-L1 expression is elevated in BRAFi-resistant melanoma cells compared to parental cells, and YAP/TAZ knockdown decreases PD-L1 expression.YAP-5SA mutant expression increases PD-L1 expression by binding to an upstream enhancer of PD-L1 gene. Notably, both BRAFi-resistant and YAP-5SA expressing melanoma cells show resistance to the cytotoxicity of Melan-A specific CD8+ T cells, inducing PD-1/PD-L1-mediated T cell suppression, and anti-PD1 blockade reverses the YAP-mediated T cell exhaustion. In addition, nuclear YAP staining in melanoma cells from clinical tumor tissues correlates with increased PD-L1 expression. Together, these findings suggest that YAP promotes PD-L1 upregulation and immune evasion in BRAFi resistance melanoma cells.