9D8U | pdb_00009d8u

CDK4 selective inhibition improves preclinical anti-tumor efficacy and safety.

Palmer, C.L., Boras, B., Pascual, B., Li, N., Li, D., Garza, S., Huser, N., Yuan, J.T., Cianfrogna, J.A., Sung, T., McMillan, E., Wei, N., Carmody, J., Kang, A.N., Darensburg, S., Dodd, T., Oakley, J.V., Solowiej, J., Nguyen, L., Orr, S.T.M., Chen, P., Johnson, E., Yu, X., Diehl, W.C., Gallego, G.M., Jalaie, M., Ferre, R.A., Cho-Schultz, S., Shen, H., Deal, J.G., Zhang, Q., Baffi, T.R., Xu, M., Roh, W., Lapira-Miller, J., Goudeau, J., Yu, Y., Gupta, R., Kim, K., Dann, S.G., Kan, Z., Kath, J.C., Nair, S.K., Miller, N., Murray, B.W., Nager, A.R., Quinlan, C., Petroski, M.D., Zhang, C., Sacaan, A., VanArsdale, T., Anders, L.

(2025) Cancer Cell 43: 464-481.e14

• PubMed: 40068598 Search on PubMed
• DOI: https://doi.org/10.1016/j.ccell.2025.02.006
• Primary Citation of Related Structures:  
  9CSK, 9D8U


• PubMed 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.

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Organizational Affiliation: 

Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA.