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.
Highlights
By focusing on an observed relationship between Polo-like kinase 1 (PLK1) inhibitors and CCNA2, we discovered that oncogenic KRAS mutation drives CCNA2 upregulation and consequent mitotic catastrophe and apoptosis in the presence of PLK1 inhibitors
We previously screened seven gastric cancer cell lines against 1345 pharmaceutical compounds and selected 63 compounds that induced a greater than 50% decrease in cell viability in at least four of the seven cell lines after 72 h of exposure [14]. We expanded this to 37 gastric cancer cell lines and to 75 compounds targeting cell proliferation, survival and signal transduction pathways (Figure 1a,b)
We generated statistical models that predicted the sensitivity of gastric cancer cells to each of the tested drugs according to mRNA-based gene expression features
Summary
Gastric cancer is one of the most common malignant tumors of the gastrointestinal track [1]. PLK1 kinase inhibitors have been developed as anticancer drugs and are currently being evaluated in clinical trials [6]: BI-2536, a dihydropteridinone compound and potent ATP-competitive PLK1 inhibitor [7], was found to inhibit cell proliferation in several human cancer cells, including breast, colon, lung, pancreas and prostate cancer [8]. Building on these results, BI-2536 became the first selective PLK1. By focusing on an observed relationship between PLK1 inhibitors and CCNA2, we discovered that oncogenic KRAS mutation drives CCNA2 upregulation and consequent mitotic catastrophe and apoptosis in the presence of PLK1 inhibitors
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