Cell-Cycle Therapeutics Come of Age

Abstract

The ability to sustain unscheduled proliferation is a hallmark of cancer. The normal process of cell division occurs via the cell cycle, a series of highly regulated steps that are orchestrated at the molecular level by specific cyclins that act in association with cyclin-dependent kinases (CDKs). Cyclin D and CDK4/6 play a key role in cell-cycle progression by phosphorylating and inactivating the retinoblastoma protein, a tumor suppressor that restrains G1- to S-phase progression. The first-generation CDK inhibitors demonstrated broad activity upon several CDKs, which likely explains their considerable toxicities and limited efficacy. Palbociclib, ribociclib, and abemaciclib represent a new class of highly specific ATP-competitive CDK4/6 inhibitors that induce reversible G1-phase cell-cycle arrest in retinoblastoma-positive tumor models. Both palbociclib and ribociclib have been approved in combination with hormone-based therapy for the treatment of naïve hormone receptor-positive advanced breast cancer on the basis of an improvement in progression-free survival. In general, CDK4/6 inhibitors are cytostatic as monotherapy but demonstrate favorable tolerability, which has prompted interest in combination approaches. Combinations with phosphatidylinositol 3-kinase and mammalian target of rapamycin inhibitors in breast cancer, and inhibitors of the RAS/RAF/mitogen-activated protein kinase pathway in RAS-mutant cancers are particularly promising approaches that are currently being evaluated. Although the subject of intense preclinical study, predictive biomarkers for response and resistance to these drugs remain largely undefined. CDK4/6 inhibitors have emerged as the most promising of the cell-cycle therapeutics and intense efforts are now underway to expand the reach of this paradigm.

Recent Advances of Cell-Cycle Inhibitor Therapies for Pediatric Cancer

“…In addition, deletion of RB1 occurs in many tumors and accelerates proliferation independently of cyclin D–CDK4/6 activity. This suggests that activation of the cyclin D/CDK4/CDK6/Rb axis is a molecular hallmark of cancer (11). Currently, three selective CDK4/6 inhibitors are approved: palbociclib (PD-0332991), ribociclib (LEE011), and abemaciclib (LY2835219).…”

“…Estrogen receptor (ER) pathway activation induces cyclin D1 and combining aromatase inhibition with CDK4/6 inhibition significantly reduces cyclin D–CDK4/6 activity (11). Palbociclib shows selective potency against CDK4 and CDK 6 (IC50 9-11 nmol/L and 15nmol/L, respectively) in comparison to a range of other kinases (12).…”

Upregulated IQUB promotes cell proliferation and migration via activating Akt/GSK3β/β‐catenin signaling pathway in breast cancer

“…Therefore, an increase in the proportion of cells at S and G2/M phase represented an enhanced proliferation of cells 22. Cyclin‐dependent kinases (CDKs), such as CDK4 and CDK6, were a family of protein kinases that were first discovered for their role in regulating the cell cycle 23, 24. Cyclin D1 forms protein complex with CDK4 or CDK6, the activity of which is necessary for cell cycle G1/S transition 25.…”

Incorporating CDK4/6 Inhibitors in the Treatment of Advanced Luminal Breast Cancer

“…The CDK inhibitor development has been a long and challenging process [4,10], until the arrival of CDK4/6 inhibitors [5,9]. Palbociclib (Ibrance ® , Pfizer, New York, NY, USA), Ribociclib (Kisqali ® , Novartis, Basel.…”

“…Different mitogenic signals converge at this level leading to the phosphorylation of the Rb protein by CDK4/6 and the subsequent release of the E2F transcription factor from pRb. E2F then triggers cell cycle progression through the transcription of key genes involved in the G1/S transition [4,5].…”