Targeting TAZ-TEAD in minimal residual disease enhances the duration of targeted therapy in melanoma models.

Targeted therapies in cancer are limited by cells exhibiting drug tolerance. We aimed to target drug tolerance in order to delay the development of acquired resistance. In melanoma, tolerance to MAPK pathway inhibitors is associated with loss of SOX10 and an enhanced TEAD transcriptional program. We show that loss of SOX10 is sufficient to up-regulate TEAD targets with dependence on the co-activator, TAZ. Active TAZ is sufficient to mediate tolerance to BRAF inhibitors and MEK inhibitors. We develop two covalent inhibitors, OPN-9643 and OPN-9652, designed to target the central palmitate binding pocket of TEADs. In SOX10-deficient cells, OPN-9643 and OPN-9652 reduce TEAD-dependent reporter activity and expression of TEAD targets, CTGF and CYR61. OPN-9643 and OPN-9652 treatment enhances the inhibitory effects of MAPK-targeted therapies in 2D and 3D growth assays in SOX10 knockout cells and reverses tolerance mediated by active TAZ. In vivo, OPN-9652 delays the onset of acquired resistance to BRAF inhibitors and MEK inhibitors from minimal residual disease. Thus, TAZ-TEAD activity plays an important role in melanoma drug tolerance and the development of acquired resistance.