Pharmacological effects of CDK4 & 6 selective inhibitor abemaciclib in hormone receptor-positive breast cancer

Chihiro Tamaki, Shin Ichi Hayashi, Aki Sato, Kaijiro Maeda, Sachi Sakaguchi, Sean Buchanan, Sotaro Enatsu

研究成果: Review article査読


Abemaciclib, a selective cyclin dependent kinases 4 and 6 (CDK4 & 6) inhibitor, is under development for the treatment of hormone receptor (HR)-positive, HER2-negative breast cancer. CDK4 & 6 inhibitors attenuate Rb phosphorylation resulting in a Gi arrest and tumor growth inhibition. Abemaciclib potently inhibits both CDK4 and CDK6, with 14-fold higher potency for CDK4-cydin D1 complexes than CDK6-cydin D3 in enzymatic assays. Low frequency of severe neutropenia requiring drug holiday in clinical trials of abemaciclib in breast cancer patients enables continuous daily dosing. Abemacidib's preclinical difference in selectivity for CDK4vs CDK6 could help explain its safety profile and ability to be dosed on a continuous schedule. Continuous inhibition of CDK4 & 6 by abemaciclib results in irreversible growth inhibition through induction of senescence and apoptosis in breast cancer cell lines. Abemaciclib shows its growth inhibitory effect particularly in estrogen receptor (ER) - positive breast cancer, and sensitivity to abemaciclib is associated with high ER levels and Rb positivity. In animals bearing ER-positive breast cancer, significant tumor growth inhibition was shown by single-agent and combination with anti-estrogen agents. Abemaciclib penetrates the blood-brain barrier and showed antitumor activity in glioma models. As described above, there are some characteristics demonstrate differences of abemaciclib and other CDK4 & 6 inhibitors. In clinical studies, abemaciclib has demonstrated efficacy and generally tolerable safety profile in HR-positive, HER2-negative breast cancer patients.

ジャーナルJapanese Journal of Cancer and Chemotherapy
出版ステータスPublished - 2019 9月

ASJC Scopus subject areas

  • 医学(全般)


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