# Targeting TEAD in melanoma drug-tolerant persister cells

> **NIH NIH F31** · THOMAS JEFFERSON UNIVERSITY · 2024 · $48,974

## Abstract

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.

## Key facts

- **NIH application ID:** 10997030
- **Project number:** 1F31CA288084-01A1
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Connor Ott
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-07-05 → 2026-07-04

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10997030

## Citation

> US National Institutes of Health, RePORTER application 10997030, Targeting TEAD in melanoma drug-tolerant persister cells (1F31CA288084-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10997030. Licensed CC0.

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