Sex Matters-Insights from Testing Drug Efficacy in an Animal Model of Pancreatic Cancer

Preclinical studies often overlook testing the efficacy of therapies across both sexes, and oncology is no exception. In a syngeneic, orthotopic model of metastasized pancreatic ductal adenocarcinoma, we assessed the impact of sex on the pathological characteristics of the disease, as well as the efficacy and potential side effects of a novel small molecule therapy that inhibits KRAS:SOS1, MEK1/2, and PI3K signaling in male and female C57BL/6J mice. The male mice exhibited less CD8-positive cell tumor infiltration, developed larger tumors, had more lung metastases, and had a lower survival probability compared to female mice. These more severe pathological features in male mice were associated with higher distress at the end of the study. The inhibitors BI-3406, trametinib, and BKM120 demonstrated synergistic effects in vitro, and the combinatorial therapy was more effective in reducing tumor weight in male mice, despite similar drug concentrations in tumors of both sexes. These findings highlight the importance of sex-specific preclinical research and provide a strong foundation for future studies with the tested compounds.