A unique CDK4/6 inhibitor: Current and future therapeutic strategies of abemaciclib.

Autor: Chong QY; Cancer Science Institute of Singapore, National University of Singapore, Singapore., Kok ZH; Cancer Science Institute of Singapore, National University of Singapore, Singapore., Bui NL; Cancer Science Institute of Singapore, National University of Singapore, Singapore., Xiang X; Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Shanghai, China., Wong AL; Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Haematology-Oncology, National University Cancer Institute Singapore, National University Health System, Singapore., Yong WP; Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Haematology-Oncology, National University Cancer Institute Singapore, National University Health System, Singapore., Sethi G; Department of Pharmacology, National University of Singapore, Singapore., Lobie PE; Cancer Science Institute of Singapore, National University of Singapore, Singapore; Tsinghua Berkeley Shenzhen Institute (TBSI), Tsinghua University, Shenzhen, China., Wang L; Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Haematology-Oncology, National University Cancer Institute Singapore, National University Health System, Singapore. Electronic address: csiwl@nus.edu.sg., Goh BC; Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Haematology-Oncology, National University Cancer Institute Singapore, National University Health System, Singapore; Department of Pharmacology, National University of Singapore, Singapore; Department of Medicine, National University Cancer Institute Singapore, National University Health System, Singapore. Electronic address: phcgbc@nus.edu.sg.
Jazyk: angličtina
Zdroj: Pharmacological research [Pharmacol Res] 2020 Jun; Vol. 156, pp. 104686. Date of Electronic Publication: 2020 Feb 14.
DOI: 10.1016/j.phrs.2020.104686
Abstrakt: Cell cycle dysregulation, characterised by aberrant activation of cyclin dependent kinases (CDKs), is a hallmark of cancer. After years of research on the first and second generations of less selective CDK inhibitors with unfavourable clinical activity and toxicity profiles, CDK4/6 inhibitors become the first and only class of highly specific CDK inhibitors being approved for cancer treatment to date. CDK4/6 inhibitors have transformed the treatment paradigm of estrogen receptor-positive (ER+) breast cancer, dramatically improving the survival outcomes of these patients when incorporated with conventional endocrine therapies in both the first and later-line settings. Currently, the efficacies of CDK4/6 inhibitors in other breast cancer subtypes and cancers are being actively explored. All three CDK4/6 inhibitors have demonstrated very similar clinical efficacies. However, being the least similar structurally, abemaciclib is the only CDK4/6 inhibitor with single agent activity in refractory metastatic ER + breast cancer, the ability to cross the blood brain barrier efficiently, and a distinct toxicity profile of lower myelosuppression such that it can be dosed continuously. Here, we further discuss the distinguishing features of abemaciclib as compared to the other two CDK4/6 inhibitors, palbociclib and ribociclib. Besides being the most potent inhibitor of CDK4/6, abemaciclib exhibits a wider selectivity towards other CDKs and kinases, and functions through additional mechanisms of action besides inducing G1 cell cycle arrest, in a dose dependent manner. Hence, abemaciclib has the potential to act independently of the CDK4/6-cyclin D-RB pathway, resulting in crucial implications on the possibly expanded clinical indications and predictive biomarkers of abemaciclib, in contrast to the other CDK4/6 inhibitors. The current status of preclinical evidence and clinical studies of abemaciclib as a single agent and in combination treatment in breast and other cancers, together with its potential predictive biomarkers, is also summarised in this review.
Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest
(Copyright © 2020 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: