Pharmacogenomic Analysis Reveals CCNA2 as a Predictive Biomarker of Sensitivity to Polo-Like Kinase I Inhibitor in Gastric Cancer

Abstract

Despite recent innovations and advances in early diagnosis, the prognosis of advanced gastric cancer remains poor due to a limited number of available therapeutics. Here, we employed pharmacogenomic analysis of 37 gastric cancer cell lines and 1345 small-molecule pharmacological compounds to investigate biomarkers predictive of cytotoxicity among gastric cancer cells to the tested drugs. We discovered that expression of CCNA2, encoding cyclin A2, was commonly associated with responses to polo-like kinase 1 (PLK1) inhibitors (BI-2536 and volasertib). We also found that elevated CCNA2 expression is required to confer sensitivity to PLK1 inhibitors through increased mitotic catastrophe and apoptosis. Further, we demonstrated that CCNA2 expression is elevated in KRAS mutant gastric cancer cell lines and primary tumors, resulting in an increased sensitivity to PLK1 inhibitors. Our study suggests that CCNA2 is a novel biomarker predictive of sensitivity to PLK1 inhibitors for the treatment of advanced gastric cancer, particularly cases carrying KRAS mutation.