The University of Texas M.D. Anderson Cancer Center Houston United States
Cyclin dependent kinase 9 CDK9 is a promising potential therapeutic target in gastric adenocarcinoma GAC because of its critical role in transcription of pleiotropic pathways involved in GAC. We hypothesize that CDK9 may be a critical mediator of growth andor metastatic progression in GAC and functional downregulation of CDK9 will inhibit local growth andor distant metastasis. Treatment of KKLS, IM95CMV-luc, MKN-45-luc, KATO-III and AGS cell lines with CDK9 inhibitor BAY1143572 demonstrated anticancer efficacy by proliferation MTS, cell cycle, and apoptosis assays p less than 0.05. Cell lysates of GAC cell treated with BAY1143572 are prepared to identify candidate CDK9-specific markers indicative of BAY1143572 efficacy by reverse phase protein assay RPPA to identify CDK9-dependent molecular targets after CDK9 inhibition. In vivo, BAY1143572 treated IM95CMV-luc and MKN-45-luc ectopic xenografts inhibited tumor growth in a dose dependent manner compared to control tumors p less than 0.05. Drug efficacy of BAY1143572 in a novel orthotopic gastroesophageal junction cancer model is currently being evaluated. Identifying trends in tumor regression local vs. metastatic induced by CDK9 inhibition will provide direction in understanding mechanism of action of CDK9 in GAC. Establishing the antitumor efficacy of BAY1143572 in the proposed experiments will pave the way for further exploration of this therapeutic strategy in GAC patients.