MCL1 and BCL-xL Levels in Solid Tumors Are Predictive of Dinaciclib-Induced Apoptosis

Dinaciclib is a potent CDK1, 2, 5 and 9 inhibitor being developed for the treatment of cancer. Additional understanding of antitumor mechanisms and identification of predictive biomarkers are important for its clinical development. Here we demonstrate that while dinaciclib can effectively block cell cycle progression, in vitro and in vivo studies, coupled with mouse and human pharmacokinetics, support a model whereby induction of apoptosis is a main mechanism of dinaciclib's antitumor effect and relevant to the clinical duration of exposure. This was further underscored by kinetics of dinaciclib-induced downregulation of the antiapoptotic BCL2 family member MCL1 and correlation of sensitivity with the MCL1-to-BCL-xL mRNA ratio or MCL1 amplification in solid tumor models in vitro and in vivo. This MCL1-dependent apoptotic mechanism was additionally supported by synergy with the BCL2, BCL-xL and BCL-w inhibitor navitoclax (ABT-263). These results provide the rationale for investigating MCL1 and BCL-xL as predictive biomarkers for dinaciclib antitumor response and testing combinations with BCL2 family member inhibitors.

Dinaciclib是一种强效的CDK1、2、5和9抑制剂，目前正在开发用于治疗癌症。对其抗肿瘤机制进行深入理解以及预测性生物标志物的鉴定对于其临床开发至关重要。本研究表明，尽管dinaciclib能够有效阻断细胞周期进程，但体外和体内研究，结合小鼠和人体药代动力学数据，支持以下模型：诱导细胞凋亡是dinaciclib抗肿瘤作用的主要机制，且与临床暴露的持续时间相关。这一结论得到dinaciclib诱导的抑制抗凋亡BCL2家族成员MCL1的动力学变化以及与体外和体内实体瘤模型中MCL1到BCL-xL mRNA比例或MCL1扩增的敏感性之间的相关性进一步证实。此外，MCL1依赖的细胞凋亡机制还得到了与BCL2、BCL-xL和BCL-w抑制剂navitoclax（ABT-263）的协同作用的支撑。这些结果为研究MCL1和BCL-xL作为dinaciclib抗肿瘤反应预测性生物标志物以及测试与BCL2家族成员抑制剂的联合用药提供了理论依据。