Targeting CDK9 and MCL-1 by a new CDK9/p-TEFb inhibitor with and without 5-fluorouracil in esophageal adenocarcinoma. (July 2019)

• Record Type: Journal Article
• Authors: Tong, Zhimin; Mejia, Alicia; Veeranki, Omkara; Verma, Anuj; Correa, Arlene M.; Dokey, Rashmi; Patel, Viren; Solis, Luisa Maren; Mino, Barbara; Kathkuda, Riham; Rodriguez-Canales, Jaime; Lin, Steven H.; Krishnan, Sunil; Kopetz, Scott; Blum, Mariela; Ajani, Jaffer A.; Hofstetter, Wayne L.; Maru, Dipen M.
• Is Part Of: Therapeutic advances in medical oncology. Volume 11(2019)
• Publication Date: 2019-07
• Subjects: adenocarcinoma -- CDK9 -- 5-fluorouracil and MCL-1 -- esophagus; Oncology -- Periodicals; Cancer -- Treatment -- Periodicals; 616.994005
• DOI: 10.1177/1758835919864850
• Languages: English
• ISSNs: 1758-8340

Abstract

Background: CDK9 inhibitors are antitumorigenic against solid tumors, including esophageal adenocarcinoma (EAC). However, efficacy of a CDK9 inhibitor combined with 5-fluorouracil (5-FU) and target proteins that are targeted by these agents in EAC are unknown. Methods: The anti-EAC efficacy of a new CDK9 inhibitor, BAY1143572, with and without 5-FU was assessed in vitro and in xenograft models in athymic nu/nu mice. Synergy between BAY1143572 and 5-FU in inhibiting cell proliferation was analyzed by calculating the combination index using CompuSyn software. Potential targets of BAY1143572 and 5-FU were identified by reverse-phase protein array. The effects of BAY1143572 and 5-FU on MCL-1 in vitro were analyzed by Western blotting, quantitative real-time polymerase chain reaction, and chromatin immunoprecipitation assay. MCL-1 protein expression in tumors from patients with locoregional EAC treated with chemoradiation and surgery was assessed by immunohistochemistry. Results: BAY1143572 had dose-dependent antiproliferative and proapoptotic effects and demonstrated synergy with 5-FU against EAC in vitro . The median volumes of FLO-1 and ESO-26 xenografts treated with 5-FU plus BAY114352 were significantly smaller than those of xenografts treated with either agent alone ( p < 0.05). BAY1143572 downregulated MCL-1 by inhibiting HIF-1α binding to the MCL-1 promoter. 5-FU enhanced BAY1143572-induced MCL-1 downregulation and stable MCL-1 overexpression reduced the apoptosis induced by BAY1143572 and 5-FU in vitro . High patients' tumor MCL-1 expression was correlated with shorter overall and recurrence-free survival. Conclusions: BAY1143572 and 5-FU have synergistic antitumorigenic effects against EAC. MCL-1 is a downstream target of CDK9 inhibitors and a predictor of response to neoadjuvant chemoradiation in EAC.