Editors' ChoiceCancer

Actin’ against BRAF inhibitors

Sci. Signal.  08 Mar 2016:
Vol. 9, Issue 418, pp. ec51
DOI: 10.1126/scisignal.aaf6186

Inhibitors against the kinase BRAF are initially effective against BRAFV600E mutant melanoma. Resistance inevitably develops, in part, because the cancer cells induce tumor-associated fibroblasts to produce stiff extracellular matrix that triggers adaptive signaling in the tumor cells (see also Zanconato and Piccolo). YAP and TAZ (collectively YAP/TAZ) are transcriptional regulators that become activated in response to changes in the cytoskeleton, which would occur upon stiffening of the extracellular matrix. Kim et al. found that inhibiting changes in the cytoskeleton of the tumor cells and thus preventing activation of YAP/TAZ may overcome drug resistance in BRAF-mutant melanoma. Prolonged exposure of cultured melanoma cells to the BRAF inhibitor vemurafenib induced drug resistance that was associated with a change in shape, increased actin polymerization, and nuclear localization and induction of the transcriptional activity of YAP/TAZ. Microarray analysis revealed that the expression of cell cycle–related genes in drug-resistant cells was YAP/TAZ-dependent. Expressing a constitutively active YAP conferred vemurafenib resistance to drug-sensitive melanoma cells, whereas silencing YAP resensitized drug-resistant cells. Indeed, knockdown of YAP and TAZ reduced cell proliferation even in the absence of vemurafenib in resistant cells. Cytochalasin D or blebbistatin, which inhibit actin polymerization or actomyosin contractility, respectively, caused YAP/TAZ to relocalize to the cytoplasm and decreased the viability of vemurafenib-resistant cells. An RNA interference–based screen indicated that TESK1, a kinase that inactivates the actin-severing protein cofilin (and thereby inhibits actin remodeling), is an enzymatic target that could be inhibited to restore vemurafenib sensitivity in melanoma. Together the findings indicate that actin remodeling in response to BRAF inhibition activates YAP/TAZ and the subsequent expression of genes promoting cell proliferation. Thus, inhibiting actin remodeling might improve therapeutic outcome for BRAF inhibitor–resistant melanoma patients.

M. H. Kim, J. Kim, H. Hong, S.‐H. Lee, J.‐K. Lee, E. Jung, J. Kim, Actin remodeling confers BRAF inhibitor resistance to melanoma cells through YAP/TAZ activation. EMBO J. 35, 462–478 (2016). [PubMed]

F. Zanconato, S. Piccolo, Eradicating tumor drug resistance at its YAP‐biomechanical roots. EMBO J. 35, 459–461 (2016). [PubMed]