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

posted on 07.10.2014, 03:18 authored by Robert N. Booher, Harold Hatch, Brian M. Dolinski, Thi Nguyen, Lauren Harmonay, Ali-Samer Al-Assaad, Mark Ayers, Michael Nebozhyn, Andrey Loboda, Heather A. Hirsch, Theresa Zhang, Bin Shi, Carrie E. Merkel, Minilik H. Angagaw, Yaolin Wang, Brian J. Long, Xianlu Q. Lennon, Nathan Miselis, Vincenzo Pucci, James W. Monahan, Junghoon Lee, Anna Georgieva Kondic, Eun Kyung Im, David Mauro, Rebecca Blanchard, Gary Gilliland, Stephen E. Fawell, Leigh Zawel, Alwin G. Schuller, Peter Strack

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.