CDK4/6 inhibition: the late harvest cycle begins

Abstract

Effective and safe pharmacologic inhibition of the cyclin dependent kinases (CDKs) has been a goal of cancer researchers for many years. CDKs are attractive therapeutic targets in cancer for two main reasons -first, some tumors harbor dependencies on particular CDKs for their initiation and maintained growth; second, there is a surprising amount of redundancy between various CDKs in maintaining normal organ function [1,2]. These observations suggest that it might be possible to inhibit a certain CDK to slow tumor growth without invoking prohibitive toxicity. Unfortunately, clinical trials using CDK inhibitors have largely failed due to low potency and specificity of the agents used.Recently, however, medicinal chemists have developed a new generation of more potent and selective CDK inhibitors. Of these, inhibitors of CDK4 and CDK6 ("CDK4/6 inhibitors") are the best characterized and have progressed furthest in clinical development. Indeed, recent trials have shown that the addition of palbociclib (a potent and selective CDK4/CDK6 inhibitor) to endocrine therapy significantly improves progression-free survival in women with advanced hormone receptor-positive breast cancer, leading to its accelerated approval by the FDA in 2015 [3]. This success has sparked enthusiasm for CDK4/6 inhibitors and a large number of trials testing CDK4/6 inhibition for a variety of tumor types have opened. Agents in development include palbociclib, abemaciclib, and ribociclib.The canonical function of CDKs 4 and 6 is to facilitate cellular transition from G1 to S phase of the cell cycle. This is achieved when levels of a D-type cyclin (cyclin D1, D2, or D3) rise in G1, facilitating formation of a cyclin D-CDK4/6 holoenzyme (also incorporating a Cip/Kip subunit such as p21 or p27) [4]. The active kinase phosphorylates the retinoblastoma tumor suppressor protein (RB), liberating RB from E2F family transcription factors. This promotes expression of genes regulating the G1-S transition. It is not surprising, therefore, that pharmacologic CDK4/6 inhibitors suppress RB phosphorylation, induce G1 arrest, and ultimately produce a senescent-like phenotype in sensitive tumor cells. Indeed, these effects alone are likely to render these agents as effective therapies for many tumors.Understanding these canonical CDK4/6 pathways might allow us to rapidly identify tumors that are likely to be sensitive to pharmacologic inhibition of these kinases. Potential candidates include: (i) tumors driven by oncogenes that are known to increase cyclin D protein EditorialFigure 1: Exploiting a non-canonical CDK4/6 pathway to overcome drug resistance. A non-canonical function of CDK4/6 that can be exploited for therapeutic benefit. Left: In a drug-resistant HER2-positive breast cancer cell, CDK4 phosphorylates RB and also interacts with TSC2. CDK4 activity enhances mTOR activity, leading to feedback suppression of upstream receptor tyrosine kinases (RTKs). Middle: When the cell is treated with a CDK4/6 inhibitor (red arrows), RB phosphorylation declines, suppre...

Aspirin regulation of c-myc and cyclinD1 proteins to overcome tamoxifen resistance in estrogen receptor-positive breast cancer cells

“…Drugs that target this axis can be used in the treatment of cancers especially breast cancer [17, 18, 44, 45]. In tamoxifen sensitive breast cancer cell line MCF-7, 4-OHT alone could down-regulate the protein level of cyclinD1, while there was no such effect observed in tamoxifen resistant cell line MCF-7/TAM.…”

“…CyclinD-CDK4/CDK6 axis has an important role in the survival and proliferation of cancer cells, which mainly takes effect through regulating the cell cycle [ 43 ]. Drugs that target this axis can be used in the treatment of cancers especially breast cancer [ 17 , 18 , 44 , 45 ]. In tamoxifen sensitive breast cancer cell line MCF-7, 4-OHT alone could down-regulate the protein level of cyclinD1, while there was no such effect observed in tamoxifen resistant cell line MCF-7/TAM.…”

CDK4/6 inhibition in breast cancer: current practice and future directions

“… 49 This pCR rate compares favorably to that observed in similar patients treated with chemotherapy and anti-HER2 therapy, and speaks to the crosstalk between CDK4/6 and HER2 signaling in breast cancer cells. 51 Table 4 outlines the ongoing randomized trials evaluating CDK4/6 inhibitors in advanced HER2-positive breast cancer patients. Included are two global, randomized trials – the MonarcHER study ( ClinicalTrials.gov identifier: NCT02675231) evaluates the role of abemaciclib in patients with pretreated metastatic disease, and the PATINA study ( ClinicalTrials.gov identifier: NCT02947685) explores the benefits of adding palbociclib to standard first-line metastatic therapy.…”

Patient-Derived Xenografts for Prognostication and Personalized Treatment for Head and Neck Squamous Cell Carcinoma

“…P16Ink4a (encoded by the CDKN2A gene) is a negative regulator of this axis. Tumors with CCND1 amplification and/or loss of CDKN2A should therefore show an increased dependence on CDK4 and/or CDK6 (Goel and Zhao, 2016). We therefore sought to use our PDX resource to determine whether alterations in these genes would confer sensitivity to the CDK4 and CDK6 inhibitor abemaciclib.…”