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
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Ther Adv Med Oncol. 2019 Jul 25;11:1758835919864850. doi: 10.1177/1758835919864850. eCollection 2019.
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.
The anti-EAC efficacy of a new CDK9 inhibitor, BAY1143572, with and without 5-FU was assessed 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 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.
BAY1143572 had dose-dependent antiproliferative and proapoptotic effects and demonstrated synergy with 5-FU against EAC . 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 ( < 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 . High patients' tumor MCL-1 expression was correlated with shorter overall and recurrence-free survival.
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.
细胞周期蛋白依赖性激酶9（CDK9）抑制剂对实体瘤具有抗肿瘤作用，包括食管腺癌（EAC）。然而，CDK9抑制剂与5-氟尿嘧啶（5-FU）联合使用的疗效以及这些药物在EAC中的靶向蛋白尚不清楚。
在无胸腺裸鼠异种移植模型中评估新型CDK9抑制剂BAY1143572单独及联合5-FU的抗EAC疗效。使用CompuSyn软件计算联合指数，分析BAY1143572与5-FU在抑制细胞增殖方面的协同作用。通过反相蛋白质阵列鉴定BAY1143572和5-FU的潜在靶点。通过蛋白质免疫印迹法、定量实时聚合酶链反应和染色质免疫沉淀试验分析BAY1143572和5-FU对髓细胞白血病-1（MCL-1）的影响。通过免疫组织化学评估接受放化疗和手术治疗的局部区域EAC患者肿瘤中MCL-1蛋白表达。
BAY1143分72具有剂量依赖性的抗增殖和促凋亡作用，并与5-FU联合对EAC显示出协同作用。5-FU加BAY114352治疗的FLO-1和ESO-26异种移植瘤的中位体积显著小于单独使用任一药物治疗的异种移植瘤（<0.05）。BAY1143572通过抑制缺氧诱导因子-1α（HIF-1α）与MCL-1启动子的结合而下调MCL-1。5-FU增强BAY1143572诱导的MCL-1下调，稳定的MCL-1过表达减少BAY1143572和5-FU诱导的凋亡。患者肿瘤MCL-1高表达与较短的总生存期和无复发生存期相关。
BAY1143572和5-FU对EAC具有协同抗肿瘤作用。MCL-1是CDK9抑制剂的下游靶点，也是EAC新辅助放化疗反应的预测指标。
