CDK4 selective inhibition improves preclinical anti-tumor efficacy and safety
Cynthia L. Palmer, Britton Boras, Bernadette Pascual, Na Li, Danan Li, Scott J. Garza, Nanni Huser, Jing Yuan, Julie Cianfrogna, Tae Sung, Elizabeth A. McMillan, Na Wei, Jason Carmody, Aubrey Nayeon Kang, Seth Darensburg, Taran Dodd, James V. Oakley, James Solowiej, Lisa Nguyen, Suvi T. M. Orr, Ping Chen, Eric W. Johnson, Xiu Yu, Wade Diehl, Gary M. Gallego, Mehran Jalaie, Rose Ann Ferre, Sujin Cho-Schultz, Hong Shen, Judith G. Deal, Qin Zhang, Timothy R. Baffi, Meirong Xu, Whijae Roh, Jennifer Lapira-Miller, Jérôme Goudeau, Yanke Yu, Rajat Gupta, Kimberly H. Kim, Stephen G. Dann, Zhengyan Kan, John C. Kath, Sajiv K. Nair, Nichol Miller, Brion W. Murray, Andrew R. Nager, Casey L. Quinlan, Matthew D. Petroski, Cathy Zhang, Aida Sacaan, Todd VanArsdale, Lars Anders
Abstract
CDK4/6 inhibitors have revolutionized treatment of hormone receptor positive (HR+), HER2 non-amplified (HER2-) breast cancer. Yet, all "dual" CDK4/6 inhibitors show common dose-limiting hematologic toxicities, foremost neutropenia. This poses challenges to provide these agents at concentrations necessary to extinguish cell cycling in tumors. HR+ breast cancer cells are highly dependent on CDK4 but not CDK6. By contrast, CDK4 is dispensable for human bone marrow derived cells, due to the primary and compensatory role of CDK6 in hematopoiesis. This prompted us to develop atirmociclib (PF-07220060), a next-generation CDK4 selective inhibitor. Atirmociclib's impact on circulating neutrophils was reduced, in proportion with its increase in CDK4 versus CDK6 selectivity. Realized dose intensification led to greater CDK4 inhibition and deeper anti-tumor responses, pointing to CDK4 target coverage as a limiting factor of CDK4/6 inhibitor efficacy. We also highlight combinatorial agents that may counter acquired resistance to CDK4 selective inhibition and widen its clinical application.