Consensus Molecular Subtypes Inform HIPEC Agent Selection in Colorectal Cancer Peritoneal Metastases.

Abstract

Although hyperthermic intraperitoneal chemotherapy (HIPEC) added to cytoreductive surgery shows promise for colorectal cancer with peritoneal metastases (CRC-PM), effectiveness remains variable. Given the predominance of consensus molecular subtype 4 (CMS4) in CRC-PM and resistance to standard agents, we hypothesized CMS4 exhibits distinct drug sensitivities. Drug sensitivity data from the DepMap PRISM Repurposing Dataset for 34 CRC cell lines were classified into the 4 CMS subtypes. Five intraperitoneal agents were analyzed: mitomycin-C, oxaliplatin, irinotecan, 5-fluorouracil, and cisplatin. Differential drug response among CMS subtypes was assessed using log2 fold change (log2FC) in cell viability. The 34 CRC cell lines were classified into 4 categories: CMS1 (29%), CMS2 (18%), CMS3 (26%), and CMS4 (26%). CMS4 cell lines demonstrated higher sensitivity than CMS2 lines to mitomycin-C (median log2FC = -2.35 versus -0.21, p = 0.019). CMS4 and CMS3 cell lines were significantly more sensitive to irinotecan than CMS1 and CMS2 cell lines (p = 0.004). Oxaliplatin, 5-fluorouracil, and cisplatin showed no differential sensitivity across subtypes. CMS4 cell lines demonstrated sensitivity (sensitivity threshold log2FC < -1.74) to mitomycin-C and irinotecan but showed lack of sensitivity to oxaliplatin, 5-fluorouracil, and cisplatin. CMS4 exhibits distinct drug sensitivity patterns that could guide personalized HIPEC agent selection. This may explain the success of mitomycin-C and the limited efficacy of oxaliplatin in HIPEC trials. Future clinical trials should consider genomic subtyping and drug sensitivity testing to guide personalized HIPEC strategies for patients with CRC-PM.