YAP-driven stemness and TEAD-induced neuroendocrine cells drive resistance to KRASG12C therapies in metastatic colorectal cancer
KRAS mutations are a predominant driver of metastatic colorectal cancer (mCRC), with approximately 10% of patients harboring the KRAS p.G12C variant. Despite the development of KRASG12C (G12Ci) and EGFR (EGFRi) inhibitors such as sotorasib and panitumumab, therapeutic resistance remains a major limitation. To define resistance mechanisms, we analyzed tissue biopsies from patients treated with G12Ci+EGFRi and employed Xenium spatial transcriptomics (Xenium ST), along with comprehensive multi-omics profiling of patient-derived xenograft (PDX) models. Known genomic alterations including NRAS p. Q61K mutations and KRASG12C amplifications were observed; however, non-genomic resistance was strongly associated with activation of the YAP-TEAD pathway. Xenium ST data revealed two key tumor subpopulations: tumor intestinal stem cells (TISCs), marked by upregulation of KRAS and YAP, and neuroendocrine-like (NE) cells, which showed KRAS upregulation alone. G12Ci+EGFRi-resistant PDX models were enriched for TISCs and associated stemness programs. The addition of a TEAD inhibitor (TEADi; IAG-933) to dual therapy induced deep tumor regression and suppressed KRAS, YAP, stemness pathways; however, NE-like cells were enriched following triple therapy. These findings suggest that TEADi enhances the efficacy of KRASG12C + EGFR inhibition by targeting TISCs but may not eliminate NE-like subpopulations, which could mediate TEAD-independent resistance and represent a therapeutic challenge. Overall design: RNA-seq profiling of a) mCRC PDX models treated with G12Ci/G12Ci+EGFRi until no response was achieved as observed by persistent tumor growth, b) mCRC PDX models treated with TEADi monotherapy and in combination with G12Ci+EGFRi for 21 days.