KRAS inhibition is an effective therapy for appendiceal adenocarcinoma

Abstract Background 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. Methods We evaluated KRAS G12D –specific (MRTX1133) and pan-KRAS inhibitor (RMC-6236) in KRAS mut organoid and orthotopic PDX models of AA. Tumor-intrinsic and microenvironmental responses were characterized using multi-omics profiling. Clinical outcomes were also assessed in six heavily pre-treated AA patients treated with KRAS inhibitors. Results MRTX1133 was highly effective for KRAS G12D organoids (IC50=4.1 nM); both KRAS G12D and KRAS G12V organoids were sensitive to RMC-6236 (IC50=4.4 nM vs 0.5 nM, respectively). In orthotopic PDX models of peritoneal carcinomatosis from AA, MRTX1133 significantly reduced tumor growth in the KRAS G12D model TM00351, and RMC-6236 reduced tumor growth in KRAS G12V model AAPDX-16. Pathologic evaluation showed dramatically reduced tumor cellularity, proliferation, and pERK expression as well as induction of apoptosis. Gene Sets Enrichment Analysis (GSEA) revealed significant downregulations of ‘E2F targets (NES=-1.9, p-adj=0.06) and the newly developed ‘RAS/ERK (NES=-2.3, p-adj=0.06)’ gene set, consistent with the observed decrease in cell proliferation. There was marked upregulation of EMT (NES=2.7, FDR