Targeting Cell Cycle Progression: CDK4/6 Inhibition in Breast Cancer

Sneha Phadke, DO; Alexandra Thomas, MD
Published: Friday, Oct 03, 2014

Abstract

Cyclin-dependent kinase (CDK) 4/6 inhibitors are novel agents that have shown promising results in the treatment of breast cancer. CDK4 and CDK6 are proteins that are part of a cell cycle regulatory pathway that also includes p16, cyclin D, and the retinoblastoma (Rb) protein. CDK4/6 inhibitors bind to CDK4 and CDK6, preventing phosphorylation of the Rb protein. This halts cell cycle progression and induces G1 cell cycle arrest. Malignant cells frequently acquire mutations in the CDK4/6 pathway, either activating mutations of CDK4/6 or mutations in CDK4/6 regulatory mechanisms, thereby conferring a growth advantage. By inhibiting CDK4/6, tumor cells are unable to exploit this pathway for cell proliferation.



In vitro studies show robust activity of CDK4/6 inhibitors in multiple types of cancer, including breast cancer. Estrogen receptor (ER)-positive luminal breast cancer cell lines were shown to be particularly sensitive to CDK4/6 inhibition. Early clinical studies have demonstrated improvement in progression-free survival with use of these agents in patients with ER-positive breast cancer. With the success of CDK4/6 inhibitors in early clinical trials, several phase 3 trials evaluating these agents in breast cancer1 are now under way, and they may soon become an important component of combination cancer therapy.
Breast Cancer

Introduction

One of the most promising novel therapies for breast cancer involves interrupting cell cycle progression through cyclin-dependent kinase (CDK) inhibition. Several agents acting on this pathway are in early- and late-phase trials. This review describes the biologic pathways involved in this therapy, reviews the status of current agents and trials, and looks at future directions for this class of drugs.

Mechanism of Action—CDK 4/6 Pathway Normal cell cycle progression is tightly regulated by several mechanisms that control cell growth and division. Alterations in these mechanisms contribute to malignant transformation of cells and uncontrolled cell proliferation. Cyclin-dependent kinases play a key role in the progression of the cell cycle from the first growth phase (G1) through the DNA synthesis (S) phase, the second growth phase (G2), and ultimately, mitosis, or (M) phase.1 Recently developed targeted therapies take aim at cell cycle pathways, such as the CDK4/6 pathway (Figure). Proteins in this cell proliferative pathway include p16, an endogenous suppressor of CDK4/6, cyclin D1, the regulatory subunit of CDK4/6, and retinoblastoma (Rb) protein, a tumor suppressor.
... to read the full story
To Read the Full Story

View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Medical Crossfire®: Where Are We Headed in the Treatment of Triple-Negative Breast Cancer?Jul 31, 20191.5
Community Practice Connections™: Evolving Applications for PARP Inhibitors in Ovarian Cancer: Building on a Solid FoundationAug 15, 20191.5
Publication Bottom Border
Border Publication
x