CDK4/6 Inhibition in Cancer: Beyond Cell Cycle Arrest

Abstract

Pharmacologic inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) have recently entered the therapeutic armamentarium of clinical oncologists, and show promising activity in patients with breast and other cancers. Although their chief mechanism of action is inhibition of retinoblastoma (RB) protein phosphorylation and thus the induction of cell cycle arrest, CDK4/6 inhibitors alter cancer cell biology in other ways that can also be leveraged for therapeutic benefit. These include modulation of mitogenic kinase signaling, induction of a senescence-like phenotype, and enhancement of cancer cell immunogenicity. We describe here the less-appreciated effects of CDK4/6 inhibitors on cancer cells, and suggest ways by which they might be exploited to enhance the benefits of these agents for cancer patients.

Estrogen receptor beta expression correlates with proliferation in desmoid tumors

“…ERα upregulates cyclin D1 in breast cancer and thus inhibition of ERα with endocrine agents results in cell cycle arrest . In hormone refractory breast cancer and other cancers, various proliferative pathways may induce cyclin D1 and Cdk 4/6, such as PI3K . Highly specific Cdk inhibitors target Cdk 4 and 6 and act synergistically with hormonal therapy in breast cancer .…”

“…7 In hormone refractory breast cancer and other cancers, various proliferative pathways may induce cyclin D1 and Cdk 4/6, such as PI3K. 8 Highly specific Cdk inhibitors target Cdk 4 and 6 and act synergistically with hormonal therapy in breast cancer. 9,10 An overall survival benefit was reported in a randomized trial with the first-in-class Cdk 4/6 inhibitor palbociclib combined with fulvestrant in locoregionally advanced or metastatic hormone receptor-positive HER2-negative breast cancer.…”

Identification of Ligand‐binding Hotspot Residues of CDK4 Using Molecular Docking and Molecular Dynamics Simulation

“…Different CDKs have different functions in various cell‐cycle phases, but all CDKs are structurally very similar . Two families of endogenous inhibitory proteins, inhibitors of CDK4 (INK4) and CDK interacting protein/kinase inhibitory protein (CIP/KIP), are important for the regulation of CDK4/6 activity . Different CDKs have unique roles at the various phases of the cell cycle.…”

“…Cyclin-dependent protein kinases (CDKs) belong to the cyclin-dependent kinases (CDKs), mitogen-activated protein kinases (MAP kinases), glycogen synthase kinases (GSK) and CDK-like kinases (CMGC) family 1 and are protein-serine/threonine kinases. 2 In humans, about 20 CDKs (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) and 13 cyclin groups (A, B, C, D, E, F, G, H, J, K, L, T, and Y) have been reported. 3 CDKs are important regulators of cell-cycle progression.…”

CDK4/6 inhibitor protects chemerin‐induced human granulosa‐lutein cells from apoptosis by inhibiting the p53/p21waf pathway

“…The phosphorylation of RB1 drives cell cycle progression from G1 to the S phase by enabling E2F transcription factors to induce coordinated transcription of genes critical for DNA synthesis and cell cycle progression (Di Fiore, D'Anneo, Tesoriere, & Vento, 2013;Johnson et al, 2016). Nonetheless, cyclin D and CDK4/6 are not universally required for progression of the cell cycle during development in most cell types (Goel et al, 2018). A number of studies have established that the CDK4/6 inhibitor palbociclib can suppress specific genes and exert strong effects on cancer progression, inflammation and cardiovascular disease (Anders et al, 2011;Preusser et al, 2018;Yin et al, 2018).…”