ABSTRACT Resistance is still a limitation of immune checkpoint antibodies and MAPK pathway-targeted inhibitors. Drug- tolerant persister cell populations are thought to contribute to the emergence of resistant tumors. Loss of the transcription factor, SOX10, and enhanced YAP/TAZ-TEAD signaling are frequently associated with acquired resistance and are associated with the minimal residual disease invasive transcriptional state. In our analysis of human patient-derived xenograft single-cell RNA-seq data, we detect elevated levels of canonical TEAD targets, CTGF and CYR61 in the SOX10-low, invasive cell state. We show that SOX10 loss is sufficient to induce a TEAD transcriptional program including CYR61 and CTGF. YAP and TAZ are paralogs that share 50% identity, but SOX10-deficient cells showed a strong dependence on TAZ for CYR61 and CTGF expression. Furthermore, overexpression of active TAZ was sufficient to mediate tolerance to BRAF inhibitors and MEK inhibitors. We developed novel covalent inhibitors, OPN-9643 and OPN-9652, designed to target the central palmitate binding pocket of TEADs. Treatment of SOX10-deficient cells with either OPN-9643 or OPN-9652 reduced CTGF and CYR61 expression as well as TEAD-dependent luciferase reporter activity. Our studies aim to utilize novel TEAD inhibitors to target SOX10-deficient drug-tolerant melanoma cells. Through this training at Thomas Jefferson University, I will learn molecular techniques, bio-informatics, develop critical thinking skills, and learn to communicate my science. This award would help me to achieve my long-term goal of becoming an independent scientist.