Role of cyclin-dependent kinase 4/6 inhibitors in the current and future eras of cancer treatment

Abstract

Cyclin-dependent kinase 4/6 inhibitors, which act by inhibiting progression from the G1 to S phases of the cell cycle, include palbociclib, ribociclib, abemaciclib, and trilaciclib. Palbociclib and ribociclib are currently food and drug administration-approved for use in combination with aromatase inhibitors in postmenopausal women with metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. Palbociclib is also food and drug administration-approved for use in combination with fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer progressing after endocrine therapy. Abemaciclib is the newest cyclin-dependent kinase 4/6 inhibitor to gain Food and Drug Administration (FDA) approval, specifically as monotherapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer previously treated with chemotherapy and endocrine therapy. Abemaciclib also shares a similar indication with palbociclib for use in combination with fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer progressing after endocrine therapy. Trilaciclib use remains largely investigational at this time. However, despite FDA-approval for only metastatic hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, all four cyclin-dependent kinase 4/6 inhibitors have shown promise in hematologic malignancies and non-breast solid tumors. Although further research is needed, cyclin-dependent kinase 4/6 inhibitors represent intriguing developments in the treatment of various malignancies, including those with such poor prognoses as glioblastoma multiforme, mantle cell lymphoma, and metastatic melanoma. We discuss the approved indications, current research, and areas of future exploration for palbociclib, ribociclib, abemaciclib, and trilaciclib.

Inhibiting CDK4/6 in Breast Cancer with Palbociclib, Ribociclib, and Abemaciclib: Similarities and Differences

“…In breast cancer, the activation of estrogen receptors as well as other proliferation-inducing signals stimulate the complexation of CDK4/6 with cyclin D1 [19]. Binding of CDK4/6 to cyclin D1 induces phosphorylation of the retinoblastoma (Rb) tumor suppressor protein, releasing its inhibitory effect and thereby providing the starting signal for cell division [16,18,[20][21][22]. Normally, CDK4 and CDK6 are inhibited by the protein p16.…”

lncRNA HNF1A‐AS1 modulates non–small cell lung cancer progression by targeting miR‐149‐5p/Cdk6

“…Cyclin‐dependent kinase 6 (Cdk6), as a catalytic subunit of protein kinase complex, is involved in the regulation of cell cycle . The inhibitors of Cdk6 were shown to be a promising agents in the treatment of various tumors via suppressing G1/S phases progression of the cell cycle. Cdk inhibition also upregulated immediate senescence of small cell lung cancer cell, and Cdk4/6 inhibitors were found to be effective on treatment of NSCLC .…”

Inhibition of UBE2N‐dependent CDK6 protein degradation by miR‐934 promotes human bladder cancer cell growth

“…CDK6 is up-regulated in several types of cancers (3,4). Recent studies showed that inhibition of CDK6 expression results in enhanced clinical treatment by breast and glioblastoma cells (36)(37)(38)(39)(40)(41)(42)(43)(44)(45). Collectively, this indicates that CDK6 may play a vital role in any clinical treatments of malignant cancers.…”