Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers

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.

Hormone Receptor–Positive, HER2-Negative Metastatic Breast Cancer: Redrawing the Lines

“…Knowledge of the molecular heterogeneity of breast cancer has led to the identification of the role that cell-cycle signalling plays in breast cancer oncogenesis-in particular, for patients with hr-positive mbca 24 . The cdks drive cell-cycle progression and control transcriptional processes 24,25 .…”

“…The cdks drive cell-cycle progression and control transcriptional processes 24,25 . The dysregulation of multiple cdk family members commonly occurs in human cancer.…”

“…The dysregulation of multiple cdk family members commonly occurs in human cancer. The cyclin D-cdk4/6-retinoblastoma protein-ink4 axis is particularly disrupted, facilitating cancer cell proliferation, thus leading to research targeting cdk 4/6 as a therapeutic approach 24,25 . Palbociclib was the first oral small-molecule cdk 4/6 inhibitor to be developed.…”

“…Palbociclib was the first oral small-molecule cdk 4/6 inhibitor to be developed. It is known to arrest cells in G1 phase by blocking phosphorylation of retinoblastoma protein at cdk 4/6-specific sites [24][25][26] . Preclinical studies suggested growth-inhibitory activity in hr-positive breast cancer cells and potential synergy with endocrine agents 26 .…”

Biomolecules and Pure Carbon Aggregates: An Application Towards “Green Electronics”

“…When irradiated using gamma rays and neutrons (non-ionizing radiation), the dynamics of DNA macromolecules [78] changes its configuration when involved in environmental interactions with other components of the living cells [79]. Whenever any radiation passes through a semiconductor device, different effects are observed which depends on the range of energy of the particle (proton, alpha, neutron and both types of beta) and rays, such as gamma radiation [80]. These include defects as: vacancies, defect clusters, dislocation loops near the surface and adjustment of band gaps [81].…”