CDK4/6 blockade in breast cancer: current experience and future perspectives

Abstract

Dysregulated cellular proliferation, one of the hallmarks of cancer, is mediated by aberrant activation of the cell cycle machinery through the biological effects of cyclin-dependent kinases (CDKs). The clinical development of non-selective CDK inhibitors failed due to combined lack of efficacy and excessive toxicity reported by clinical trials across different cancer types. The clinical development of second generation, CDK4/6-selective inhibitors, namely palbociclib, abemaciclib and ribociclib, led to practice-changing results in the setting of breast cancer. Areas covered: This review illustrates how CDK4/6-selective inhibitors got approval for the treatment of patients with either newly diagnosed or pretreated advanced hormone receptor positive, HER2-negative breast cancer. Furthermore, data about potential predictive biomarkers, as well as preclinical and preliminary clinical evidence for potential antitumor activity of CDK4/6 inhibition in other breast cancer subtypes is provided. Expert opinion: Future clinical development of CDK4/6 inhibitors in breast cancer will focus on the following aspects: i) optimization of treatment sequencing for patients with advanced disease, ii) early-stage disease, iii) other subtypes of breast cancer in rationally chosen therapeutic combinations and iv) the identification of predictive biomarkers.

HOTAIR, a long noncoding RNA, is a marker of abnormal cell cycle regulation in lung cancer

“…41,42 While Roger PP's group supposed the phosphorylated CDK4 could potentially predict sensitivity to CDK4/6 blockade, 43 this was not confirmed later in clinical results. 44…”

“…However, the clinical trial PALOMA‐1 identified that they had no association with PD 0332991 . While Roger PP's group supposed the phosphorylated CDK4 could potentially predict sensitivity to CDK4/6 blockade, this was not confirmed later in clinical results . Wang et al (2017) examined whether the expression of cyclin D3 and CDK6 is associated with palbociclib or ribociclib treatment through depletion of the antioxidants NADPH and glutathione .…”

miR-623 suppresses cell proliferation, migration and invasion through direct inhibition of XRCC5 in breast cancer

“…It is well known that CDK4 and its functional homologue CDK6 play key roles in mammalian cell proliferation, where they help drive the progression of cells into the DNA synthesis (S) phase of the cell-division cycle. Additionally, the cyclin D1–CDK4/6 axis plays a central role in breast cancer development and maintenance [ 19 – 22 ]. Therefore, we conclude that the suppressive effects of CDK4 and CDK6 expression by miR-623 not only affect cancer cell proliferation, but also influence cancer cell migration and invasion.…”

New landscapes and horizons in hepatocellular carcinoma therapy

“…Palbociclib (PD-0332991; Ibrance®, Pfizer), is a reversible, selective CDK4/6 inhibitor. Palbociclib has been recently approved by the US FDA for treatment of patients with breast cancer [169]. In HCC cell lines, palbociclib promotes a reversible cell cycle arrest and the induction of cellular senescence, alone or in association with sorafenib [170] and enhances radiosensitivity [171].…”