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

<div><p>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, <i>in vitro</i> and <i>in vivo</i> 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 <i>BCL2</i> family member <i>MCL1</i> and correlation of sensitivity with the <i>MCL1</i>-to-<i>BCL-xL</i> mRNA ratio or <i>MCL1</i> amplification in solid tumor models <i>in vitro</i> and <i>in vivo</i>. 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 <i>MCL1</i> and <i>BCL-xL</i> as predictive biomarkers for dinaciclib antitumor response and testing combinations with BCL2 family member inhibitors.</p></div>