CDK4 selective inhibition improves preclinical anti-tumor efficacy and safety

Cancer Cell, Journal Year: 2025, Volume and Issue: 43(3), P. 464 - 481.e14

Published: March 1, 2025

Highlights•Atirmociclib (PF-07220060) is a next-generation CDK4 selective inhibitor•Impact reduction on neutrophils was in proportion to increase selectivity•Greater target coverage results deeper anti-tumor responses•Combinatorial agents further atirmociclib efficacySummaryCDK4/6 inhibitors have revolutionized treatment of hormone receptor positive (HR+), HER2 non-amplified (HER2−) breast cancer. Yet, all "dual" CDK4/6 show common dose-limiting hematologic toxicities, foremost neutropenia. This poses challenges provide these at concentrations necessary extinguish cell cycling tumors. HR+ cancer cells are highly dependent but not CDK6. By contrast, dispensable for human bone marrow derived cells, due the primary and compensatory role CDK6 hematopoiesis. prompted us develop (PF-07220060), inhibitor. Atirmociclib's impact circulating reduced, with its versus selectivity. Realized dose intensification led greater inhibition responses, pointing as limiting factor inhibitor efficacy. We also highlight combinatorial that may counter acquired resistance widen clinical application.Graphical abstract

Language: Английский

Extracellular Vesicle-Derived miRNAs in Ischemic Stroke: Roles in Neuroprotection, Tissue Regeneration, and Biomarker Potential

Cellular and Molecular Neurobiology, Journal Year: 2025, Volume and Issue: 45(1)

Published: March 31, 2025

Language: Английский