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Single-cell RNAseq of from murine pancreas tumor (FPC)

ABSTRACT: Oncogenic KRAS drives pancreatic ductal adenocarcinoma (PDAC), yet resistance to RAS antagonists limits benefit. We deployed two complementary preclinical PDAC models, including a degron-regulated KRASG12D-dependent transplantation model, and a KrasG12V-driven PDAC mouse model treated with the RAS(ON) multi-selective inhibitor, RMC-7977, to describe therapeutic response and resistance mechanisms. KRASG12D degradation provoked RAS-dependent relapse, characterized by compensatory wild-type (WT) RAS upregulation, restored MAPK signaling and proliferation, and a shift towards hybrid cancer cell states. RMC-7977 treatment triggered rapid RAS-independent resistance within 7 days, distinguished by suppressed MAPK yet restored proliferation with increased epithelial differentiation, and upregulation of Fyn. Antagonists of WT RAS or FYN attenuated resistance; and combining FYN antagonism with RMC-7977 prevented the uncoupling of MAPK signaling from cell proliferation in the respective KrasG12V PDAC model. Our findings identify distinct adaptive pathways orchestrating RAS-dependent versus RAS-independent resistance in PDAC and propose combination strategies for clinical evaluation to enhance KRAS-directed therapy durability.

ORGANISM(S): Mus musculus

PROVIDER: GSE315796 | GEO | 2026/09/07

REPOSITORIES: GEO

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Project description:Appendiceal adenocarcinoma (AA) is a rare cancer with limited treatment options. KRAS is the most commonly mutated gene in AA and a promising therapeutic target, but its preclinical and translational relevance in AA remains unclear. We evaluated KRASG12D–specific (MRTX1133) and pan-KRAS inhibitor (RMC-6236) in KRASmut organoid and PDX models of AA. Tumor-intrinsic and microenvironmental responses were characterized using multi-omics profiling. MRTX1133 was highly effective for KRASG12D organoids (IC50 = 4.1 nM); both KRASG12D and KRASG12V organoids were sensitive to RMC-6236 (IC50 = 4.4 nM vs. 0.5 nM, respectively). In PDX models of peritoneal carcinomatosis from AA, MRTX1133 reduced tumor growth in the KRASG12D model TM00351, and RMC-6236 reduced tumor growth in KRASG12V model AAPDX-16. Pathologic evaluation showed dramatically reduced tumor cellularity, proliferation, and pERK expression as well as induction of apoptosis. Gene Set Enrichment Analysis (GSEA) demonstrated consistent downregulation of E2F targets and RAS/ERK signaling across both models, confirming on-target KRAS inhibition, alongside upregulation of EMT (Epithelial-to-Mesenchymal Transition), suggesting a shared resistance-associated transcriptional program. Interferon-alpha and interferon-gamma signaling were significantly upregulated following pan-KRAS inhibition, implicating TME (Tumor Microenvironment) immunomodulation as a downstream consequence of KRAS inhibition in AA. scRNA-seq analysis of the TME showed a dramatic shift from normal to inflammatory cancer-associated fibroblasts (iCAFs) following KRAS inhibition. Upregulation of interferon alpha and gamma pathways was also observed, suggesting that KRAS inhibition can activate innate immune response in the setting of peritoneal metastases. While effective suppression of RAS/ERK signaling by KRAS inhibitors reduces tumor growth, adaptive activation of the EMT pathway may mediate resistance in KRASmut AA. Additionally, KRAS inhibition remodels TME and may enhance innate immune signaling. These findings support the continued clinical development of KRAS inhibitors in AA and provide a rationale for combination strategies targeting resistance pathways and stromal remodeling.

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Single-cell RNAseq of from murine pancreas tumor (FPC)

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