CDK4 selective inhibition improves preclinical anti-tumor efficacy and safety
Cynthia L Palmer1, Britton Boras1, Bernadette Pascual1
1Pfizer Global Research and Development La Jolla, 10770 Science Center Drive, San Diego, CA 92121, USA.
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.
Insights
A new drug, atirmociclib, selectively targets CDK4, reducing neutropenia common with dual CDK4/6 inhibitors. This selectivity allows for dose intensification, improving anti-tumor responses in HR+ breast cancer.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have transformed hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer treatment.
- Dose-limiting hematologic toxicities, particularly neutropenia, limit the efficacy of current dual CDK4/6 inhibitors.
- HR+ breast cancer cells rely on CDK4, while hematopoiesis primarily utilizes CDK6, suggesting a therapeutic window for CDK4-selective agents.
Purpose of the Study:
- To develop and evaluate atirmociclib (PF-07220060), a next-generation inhibitor selective for CDK4 over CDK6.
- To assess the impact of CDK4 selectivity on hematologic toxicity and anti-tumor efficacy.
- To explore strategies for overcoming acquired resistance to CDK4-selective inhibition.
Main Methods:
- Development of atirmociclib, a novel CDK4-selective inhibitor.
- Preclinical evaluation of atirmociclib's selectivity and in vivo efficacy in breast cancer models.
- Assessment of hematologic effects, specifically neutropenia, in relation to CDK4/6 inhibition.
- Investigation of potential combinatorial therapies to address acquired resistance.
Main Results:
- Atirmociclib demonstrated enhanced selectivity for CDK4 compared to CDK6.
- Reduced impact on circulating neutrophils was observed with atirmociclib, correlating with its selectivity.
- Dose intensification of atirmociclib led to deeper CDK4 inhibition and enhanced anti-tumor responses.
- CDK4 target coverage was identified as a potential limiting factor for CDK4/6 inhibitor efficacy.
Conclusions:
- Atirmociclib represents a promising next-generation CDK4-selective inhibitor with a potentially improved safety profile regarding neutropenia.
- Selective CDK4 inhibition allows for dose intensification, leading to greater target engagement and improved anti-tumor activity in HR+ breast cancer.
- Further research into combinatorial strategies is warranted to broaden the clinical application and overcome resistance to CDK4-selective therapies.
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