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. 2025 Mar 10;43(3):464-481.e14.
doi: 10.1016/j.ccell.2025.02.006.

CDK4 selective inhibition improves preclinical anti-tumor efficacy and safety

Cynthia L Palmer  1 , Britton Boras  1 , Bernadette Pascual  1 , Na Li  1 , Danan Li  1 , Scott Garza  1 , Nanni Huser  1 , Jing Tang Yuan  1 , Julie A Cianfrogna  1 , Tae Sung  1 , Elizabeth McMillan  1 , Na Wei  1 , Jason Carmody  1 , Aubrey Nayeon Kang  1 , Seth Darensburg  1 , Taran Dodd  1 , James V Oakley  1 , James Solowiej  1 , Lisa Nguyen  1 , Suvi T M Orr  1 , Ping Chen  1 , Eric Johnson  1 , Xiu Yu  1 , Wade C Diehl  1 , Gary M Gallego  1 , Mehran Jalaie  1 , Rose Ann Ferre  1 , Sujin Cho-Schultz  1 , Hong Shen  1 , Judith G Deal  1 , Qin Zhang  1 , Timothy R Baffi  1 , Meirong Xu  1 , Whijae Roh  1 , Jennifer Lapira-Miller  1 , Jerome Goudeau  1 , Yanke Yu  1 , Rajat Gupta  1 , Kimberly Kim  1 , Stephen G Dann  1 , Zhengyan Kan  1 , John C Kath  1 , Sajiv K Nair  1 , Nichol Miller  1 , Brion W Murray  1 , Andrew R Nager  1 , Casey Quinlan  1 , Matthew D Petroski  1 , Cathy Zhang  1 , Aida Sacaan  1 , Todd VanArsdale  1 , Lars Anders  2
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Free article

CDK4 selective inhibition improves preclinical anti-tumor efficacy and safety

Cynthia L Palmer et al. Cancer Cell. .
Free article

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.

Keywords: CDK4; CDK6; PF-07220060; atirmociclib; breast cancer; cell cycle; cell cycle inhibitor; cyclin D1; cyclin-dependent kinase; neutropenia.

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Conflict of interest statement

Declaration of interests All authors listed on this manuscript are/were paid employees and/or owned stock of Pfizer, Inc. during data collection, analysis, and interpretation of their contributions. L.A. and T.V. are inventors on International Patent Publication WO 2023/100134; L.A., D.L., K.K., and E.M. on WO 2022/034504; C.L.P., M.J., P.C., S.C.-S., J.G.D., G.M.G., S.T.M.O., and S.K.N. on WO 2019/207463.

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