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

[BACKGROUND] 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.

[MATERIALS AND METHODS] 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.

[RESULTS] 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.

[CONCLUSIONS] 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.