Actin remodeling confers BRAF inhibitor resistance to melanoma cells through YAP/TAZ activation

Abstract

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. Here, 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 the 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 reduces the viability of resistant melanoma cells, whereas overexpression of constitutively active YAP induces resistance. Moreover, inhibition of actin polymerization and actomyosin 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 potential strategy to suppress resistance in BRAF inhibitor therapies.

Augmentation of the therapeutic efficacy of WEE1 kinase inhibitor AZD1775 by inhibiting the YAP–E2F1–DNA damage response pathway axis

“…The tolerability and efficacy of AZD1775–dasatinib therapy in vivo are keys to applying this therapy in the future. Because YAP is involved in resistance to molecular targeted drugs , our findings might expand the application of dasatinib as a chemosensitiser to subsets of molecular targeted drugs by inhibiting YAP function.…”

ERK and p38 MAPK Activities Determine Sensitivity to PI3K/mTOR Inhibition via Regulation of MYC and YAP

“…Furthermore, ERK-pathway has been shown to stabilize MYC protein (39, 40), and the RAS-pathway has been implicated in YAP protein stabilization (41). However, YAP has been shown to promote resistance to RAF/MEK-targeted cancer therapies in RAS mutant tumors (42, 43) and to rescue cancer cells after KRAS loss (44, 45), suggesting that YAP can be regulated at several levels to promote resistance to multiple targeted therapies.…”

Transcription factors as critical players in melanoma invasiveness, drug resistance, and opportunities for therapeutic drug development

“…Consistent with this hypothesis, the expression of SOX10 in LOXIMVI melanoma cells (lacking SOX10 and expressing high EGFR levels) increased their sensitivity to vemurafenib (Sun et al., ). In SKMEL28 and WM3248 melanoma cells, the acquisition of vemurafenib resistance was also associated with diminished expression of SOX10 (Ji et al., ; Kim et al., ). The demonstration that SOX10 knockdown results in the activation of EGFR, PDGFRβ, and ERBB3 suggests that SOX10 decrease in vemurafenib‐resistant melanoma cells positively affects not only expression of the RTKs but also their activation level (Sun et al., ).…”