G2M checkpoint pathway alone is associated with drug response and survival among cell proliferation-related pathways in pancreatic cancer.

Given the severe side effects of the treatments and poor survival, prognostic and predictive biomarkers to guide management of pancreatic cancer are in critical need. We hypothesized that cell proliferation-related pathways are associated with drug response and survival in pancreatic cancer. Six Hallmark cell proliferation-related gene sets (G2M Checkpoint, E2F Targets, MYC Targets V1 and V2, Mitotic Spindle, p53 pathway) defined by MSigDB in gene set variant analysis were evaluated in 3 independent cohorts- TCGA-PAAD (n = 176), GSE57495 (n = 63), and GSE62452 (n = 69). G2M and E2F, as well as Mitotic and p53 pathway correlated highly with other gene sets. All pathways were significantly correlated with MKI67 expression and its proliferation score, but none with cytolytic activity and the rate of pathologically complete resection (R0). All pathways were significantly associated with high alteration and expression of KRAS gene except for MYC v1. G2M, E2F, and p53 pathway were significantly associated with high alteration of TP53 gene. Interestingly, different pathways correlated with the AUC of different cancer therapeutics, such as Gemcitabine (Mitotic: r = 0.706 [P = 0.01]), Paclitaxel (MYC v2: r = -0.636 [P < 0.05]), Apatinib (Mitotic: r = -0.556 [P = 0.03]), Palbociclib (E2F: r = 0.675 [P < 0.01]), and Sorafenib (G2M: r = -0.593 [P = 0.03]). Among all six pathways, only G2M was consistently associated with worse patient survival in all three cohorts. In conclusion, each cell proliferation-related pathway was predictive of a unique agent, and the G2M score alone predicts survival in pancreatic cancer. AJCR