GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE336nnn/GSE336609/primaryOK200Transcriptomics Mus musculusHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE336609GEOGSEfalseKRAS inhibition is an effective therapy for appendiceal adenocarcinomaAppendiceal 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.2026/06/25GSE336609GSM9838793GSM9838794GSM9838795GSM9838796GSM9838790GSM9838791GSM9838792GSM9838801GSM9838802GSM9838803GSM9838804GSM9838797GSM9838786GSM9838787GSM9838798GSM9838788GSM9838799GSM9838800GSM9838789GSM9838805GSM9838806GSM98388072467624247336609 Mus musculusHomo sapiens