Abstract 3859: Targeting CDK9 and MCL-1 by a New CDK9/p-TEFB Inhibitor with and without 5-fluorouracil in esophageal adenocarcinoma

Abstract

Abstract Background: CDK9 inhibitors are anti-tumorigenic against several solid tumors including esophageal adenocarcinoma (EAC). However, efficacy of CDK9 inhibitor as adjuvant to chemotherapy and target proteins shared between these two drugs are not known. Methods: Efficacy of a new CDK9 inhibitor, BAY1143572 with and without 5-fluorouracil (5-FU) on tumor growth was tested in vitro and xenograft models of EAC. We tested effects of these agents on MCL-1 in vitro. We also analyzed a possible role of MCL-1 as a predictor of survival in patients with EAC. Results: BAY1143572 had a dose-dependent anti-proliferative and pro-apoptotic effects in vitro. BAY1143572 and 5-FU had strong synergy in vitro. Median tumor volume of FLO1 or ESO26 xenografts in cohort treated with combination of two drugs was 82% or 55% smaller than the cohort treated with 5-FU alone, and 46 % or 33% smaller than the cohort treated with BAY114352 alone (p<0.05). BAY1143572 transcriptionally downregulated MCL-1 by inhibiting HIF-1α binding to the MCL-1 promoter. 5-FU enhanced BAY1143572 induced MCL-1 downregulation in vitro. Stable overexpression of MCL-1 reduced apoptosis by BAY1143572 and 5-FU. Higher tumor cell MCL-1 expression correlated with shorter overall survival in patients with EAC treated with chemoradiation and surgery. Conclusion: CDK9 inhibitor and 5-FU are synergistic and MCL-1 is a target of CDK9 inhibitor in EAC. Citation Format: zhimin Tong, Alicia Mejia, Omkara Veeranki, Anuj Verma, Arlene Correa, Viren Patel, Rashmi Dokey, Luisa Solis, Barbara Mino, Riham Kathkuda, Jaime Canales, Steven Lin, Sunil Krishnan, Scott Kopetz, Mariela Blum, Jaffer Ajani, Wayne Hofstetter, Dipen M Maru. Targeting CDK9 and MCL-1 by a New CDK9/p-TEFB Inhibitor with and without 5-fluorouracil in esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3859.