2026 Theses Doctoral

Combined TEAD, RAS and Stroma Targeting for KRAS-mutant Cholangiocarcinoma

Sun, Qiuyan

Despite potent effects, prolonged RAS inhibitor (RASi) therapy triggers adaptive resistance and therapeutic failure. Here, we investigated mechanisms driving these adaptations, employing Cholangiocarcinoma (CCA), an aggressive liver malignancy with limited treatment options, as model system for tumor- and stroma-selective in vivo perturbations. In vivo CRISPRi identified TEAD transcription factors as tumor-intrinsic regulators of the malignant state whose critical role was amplified by RASi therapy. RAS and TEAD inhibition synergized, prolonging survival.

However, tumors ultimately adapted through stromal remodeling, characterized by an expansion of cancer-associated fibroblasts (CAFs) and increased hepatocyte growth factor (HGF) expression. Genetic depletion of CAFs or CAF-derived HGF or pharmacological inhibition of HGF receptor MET effectively overcame resistance to RASi+TEADi therapy, significantly extending survival in multiple KRAS-mutant malignancies and achieving up to 85% long-term survival in CCA models. Collectively, our study reveals a multi-layered adaptive tumor-stroma network, rather than simple restoration of oncogenic signaling, as driver of RASi resistance, and identifies KRAS, TEADs and HGF-MET as convergent therapeutic vulnerabilities. Together, these findings establish a preclinical framework for rational combination therapies of KRAS-mutant tumors.