Combined AURKA and H3K9 Methyltransferase Targeting Inhibits Cell Growth By Inducing Mitotic Catastrophe.

摘要: The current integrative pathobiologic hypothesis states that pancreatic cancer (PDAC) develops and progresses in response to an interaction between known oncogenes downstream epigenomic regulators. Congruently, this study tests a new combinatorial therapy based on the inhibition of Aurora kinase A (AURKA) oncogene one its targets, H3K9 methylation-based epigenetic pathway. This therapeutic combination is effective at inhibiting vitro growth PDAC cells both, monolayer culture systems, three-dimensional spheroids organoids. also reduces xenografts vivo Mechanistically, it was found methyltransferases pathway cells, which are arrested G2-M after targeting AURKA, decreases methylation centromeres, induces mitotic aberrations, triggers aberrant check point response, ultimately leads catastrophe. Combined, these data describe for first time hypothesis-driven design efficient treatment targets dual oncogenic-epigenomic inhibit cell via cytotoxic mechanism involves perturbation normal progression end Therefore, knowledge has significant mechanistic value as relates development therapies well biomedical relevance.Implications: These results outline model combined genetic-to-epigenetic suggest important provocative consideration harnessing capacity cell-cycle inhibitors enhance future use inhibitors. Mol Cancer Res; 15(8); 984-97. ©2017 AACR.