Pyroptosis and gasdermin expression in metastatic colorectal cancer.

Abstract

211 Background: Pyroptosis is a lytic and inflammatory form of programmed cell death mediated by gasdermin proteins. It may play an important role in cancer pathogenesis, metastasis, and modulation of the tumor immune microenvironment. However, the roles of pyroptosis and gasdermins in colorectal cancer (CRC) remain incompletely defined. We evaluated the prognostic significance of gasdermin expression in patients with metastatic CRC (mCRC) treated on CALGB (Alliance)/SWOG 80405. Methods: RNA sequencing was performed on tumors from 433 patients with mCRC in CALGB/SWOG (Alliance) 80405 who received first line FOLFOX or FOLFIRI with bevacizumab (n = 226) or cetuximab (n = 207). RNA was extracted from FFPE tumor samples and sequenced on HiSeq 2500 platform (Illumina). Expression of five gasdermin proteins (GSDMA, GSDMB, GSDMC, GSDMD, and GSDME) were stratified into tertiles. Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier and Cox regression analyses. Results: High GSDME expression was associated with shorter survival (PFS HR 1.50, 95% CI 1.18-1.90, p=0.003; OS HR 1.64, 95% CI 1.28-2.11, p=0.00012). The effect was most pronounced with cetuximab (median OS 23.1 vs 39.1 mo; HR 2.04, 95% CI 1.40-2.98, p = 0.00065), while treatment with bevacizumab showed a similar but non-significant trend (median OS 25.6 vs 34.1 mo; HR 1.31, 95% CI 0.93-1.85, p = 0.051). Conversely, high GSDMC expression was associated with longer OS in the bevacizumab arm (median 38.6 vs 29.1 mo; HR 0.66, 95% CI 0.46-0.96, p = 0.0028), but not in patients treated with cetuximab. Expression of GSDMA, GSDMB and GSDMD showed no consistent associations with survival. Conclusions: In mCRC, gasdermin expression patterns highlight the dual roles of pyroptosis in tumor biology. GSDME was associated with poor prognosis, particularly in patients receiving cetuximab, suggesting a potential relationship with EGFR signaling or resistance. In contrast, GSDMC expression trended toward improved survival and conferred benefit in the bevacizumab subgroup, pointing to context-dependent effects possibly related to angiogenesis. These findings suggest pyroptosis as a clinically relevant pathway in CRC and support further investigation of gasdermins as prognostic biomarkers and potential therapeutic targets. Trial identifiers: NCT00265850; Support: P30CA014089, U10CA180821, U10CA180882, U10CA180820 and UG1CA233277; U10CA180888; Pfizer, Genentech. https://acknowledgments.alliancefound.org Clinical trial information: NCT00265850 .