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

Zhimin Tong; Alicia Mejia; Omkara Veeranki; Anuj Verma; Arlene M Correa; Rashmi Dokey; Viren Patel; Luisa Maren Solis; Barbara Mino; Riham Kathkuda; Jaime Rodriguez-Canales; Steven H Lin; Sunil Krishnan; Scott Kopetz; Mariela Blum; Jaffer A Ajani; Wayne L Hofstetter; Dipen M Maru

doi:10.1177/1758835919864850

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

Ther Adv Med Oncol. 2019 Jul 25:11:1758835919864850. doi: 10.1177/1758835919864850. eCollection 2019.

Authors

Zhimin Tong¹, Alicia Mejia¹, Omkara Veeranki¹, Anuj Verma², Arlene M Correa³, Rashmi Dokey¹, Viren Patel¹, Luisa Maren Solis², Barbara Mino², Riham Kathkuda², Jaime Rodriguez-Canales², Steven H Lin⁴, Sunil Krishnan⁴, Scott Kopetz⁵, Mariela Blum⁵, Jaffer A Ajani⁵, Wayne L Hofstetter³, Dipen M Maru⁶

Affiliations

¹ Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
² Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
³ Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁴ Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁵ Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁶ Division of Pathology and Laboratory Medicine, Unit 085, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.

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.

Keywords: 5-fluorouracil and MCL-1; CDK9; adenocarcinoma; esophagus.

Abstract

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