The Strange Case of CDK4/6 Inhibitors: Mechanisms, Resistance, and Combination Strategies

Abstract

CDK4/6 inhibitors have emerged as a powerful class of agents with clinical activity in a number of malignancies. Targeting the cell cycle represents a core attack on a defining feature of cancer. However, the mechanisms through which selective CDK4/6 targeted agents act has few parallels in the current pharmaceutical armamentarium against cancer. Notably, CDK4/6 inhibitors act downstream of most mitogenic signaling cascades, which have implications both related to clinical efficacy and resistance. Core knowledge of cell cycle processes has provided insights into mechanisms of intrinsic resistance to CDK4/6 inhibitors; however, the basis of acquired resistance versus durable response is only beginning to emerge. This review focuses on the mechanism of action and biomarkers to direct the precision use of CDK4/6 inhibitors and rationally-developed combination therapies.

Keywords: Breast Cancer; Cell Cycle; Cyclin D1; E2F; RB.

Figures

Figure 1. Signaling integration through the CDK4/6-RB pathway

Mitogenic signals and anti-proliferative signals are integrated to yield the expression of D-type cyclins and the activation state of CDK4/6. The active kinase complex can then initiate the phosphorylation of RB and the release from the E2F family of transcription factors. These actions can be counter-balanced by the activity of physiological CDK4/6 inhibitors exemplified by p16ink4a. The E2F family of transcription factors coordinates a gene expression program that is required for features of cell cycle progression, DNA replication, and mitosis. Thus, the pathway serves to integrate signal transduction in controlling cell division. Genetic events that impact directly on CDK4/6, the inhibitors of the active complex, or disease relevant substrates are shown. Data is summarized from TCGA data deposited in cbioportal (www.cbioportal.org) and impacts on multiple organi systems.

Figure 2. Oncogenic pathways impinging on CDK4/6

Signaling pathways associated with tumorigenisis that represent common therapeutic targets are shown. These signaling pathways yield an induction of CDK4/6 activity through the stimulation of cyclin D expression. Representative therapeutic agents blunt this signaling, and yield cell cycle inhibition through multiple mechanisms including the attenuation of cyclin D1. In contrast the pharmaceutical inhibitors palbociclib, ribociclib and abemaciclib directly inhibit CDK4/6 activity to elicit the suppression of proliferation. Oncogenic stresses also impact on CDK4/6 activity. In this context, while mitogenic signaling is intact and D-type cyclins are expressed, CDK4/6 activity is inhibited through the action of endogenous inhibitors (e.g. p16ink4a).

Figure 3. Adaptive responses to CDK4/6 inhibition

In multiple models the inhibition of CDK4/6 inhibition in the face of oncgenic signals results in increased cyclin D1 expression. The adaptive responses to CDK4/6 inhibition includes enhanced MTOR or PI3K activity are associated with acquired resistance which can be prevented through the use of combination treatment that incorporate CDK4/6 inhibitors with PI3K or MTOR inhibitors. In other settings the treatment with CDK4/6 inhibition elicits the inhibition of MTOR activity that is associated with durable response or senescence.