Abstract
Despite significant advances in early detection and treatment, breast cancer still remains a major cause of morbidity and mortality for women. Our understanding of the molecular heterogeneity of the disease has significantly expanded over the past decade and the role of cell cycle signaling in both breast cancer oncogenesis and anti-estrogen resistance has gained increasing attention. The mammalian cell cycle is driven by a complex interplay between cyclins and their associated cyclin-dependent kinase (CDK) partners, and dysregulation of this process is one of the hallmarks of cancer. Despite this, initial results with broadly acting CDK inhibitors were largely disappointing. However, recent preclinical and phase I/II clinical studies using a novel, oral, reversible CDK4/6 inhibitor, palbociclib (PD-0332991), have validated the role of CDK4/6 as a potential target in estrogen receptor-positive (ER+) breast cancers. This review highlights our current understanding of CDK signaling in both normal and malignant breast tissues, with special attention placed on recent clinical advances in inhibition of CDK4/6 in ER+ disease.
Highlights
Breast cancer is a global disease, with a yearly incidence of over 1.3 million, accounting for over 23 % of all malignancies [1]
There was a significant improvement in progression-free survival (PFS) in part 1 with the median PFS increasing from 5.7 months with letrozole alone to over 18 months with the combination, resulting in a hazard ratio (HR) of 0.35 (95 % confidence interval (CI) 0.17–0.72, P = 0.06)
The preclinical observation that palbociclib (PD-0332991) had preferential activity in cell line models that represented the Estrogen receptor (ER)+ as well as HER2amplified subgroups has led to very promising phase II efficacy/safety data in ER+ breast cancers
Summary
Breast cancer is a global disease, with a yearly incidence of over 1.3 million, accounting for over 23 % of all malignancies [1]. Alterations in several cell cycle regulatory proteins have been described, including various cyclins, CDKs, and the RB gene product (pRb) [5,6,7]. The development of more specific CDK inhibitors has renewed interest in targeting the cell cycle as a novel therapeutic approach in cancer.
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