CDK4, CDK6/cyclin-D1 Complex Inhibition and Radiotherapy for Cancer Control: A Role for Autophagy

Abstract

The expanding clinical application of CDK4- and CDK6-inhibiting drugs in the managements of breast cancer has raised a great interest in testing these drugs in other neoplasms. The potential of combining these drugs with other therapeutic approaches seems to be an interesting work-ground to explore. Even though a potential integration of CDK4 and CDK6 inhibitors with radiotherapy (RT) has been hypothesized, this kind of approach has not been sufficiently pursued, neither in preclinical nor in clinical studies. Similarly, the most recent discoveries focusing on autophagy, as a possible target pathway able to enhance the antitumor efficacy of CDK4 and CDK6 inhibitors is promising but needs more investigations. The aim of this review is to discuss the recent literature on the field in order to infer a rational combination strategy including cyclin-D1/CDK4-CDK6 inhibitors, RT, and/or other anticancer agents targeting G1-S phase cell cycle transition.

Keywords: autophagy; cyclin inhibitors; radiotherapy.

Figure 1

Schematic overview of cell cycle regulation, with an emphasis on radiotherapy-induced pathways and CDK/cyclin regulation. In M phase and in G2 resting phase, cancer cells are respectively very sensitive and moderately sensitive to radiation injury, whereas in G1 phase and in S phase, cancer cells are moderately resistant to radiation injury. Irradiation induces G1 and G2 cell cycle checkpoint activation and DNA repair. Most cancer cells are defective in G1 checkpoint, commonly due to the mutations/alterations of the key regulators of the G1 checkpoint, but contain a functional G2 checkpoint.

Figure 2

Chemical structures of cyclin inhibitors that are currently approved.

Figure 3

A simplified overview of the role of autophagy and Beclin-1 in CCND1 degradation, as a possible mechanism actionable for G 1/S cell cycle arrest in cancer. Radiation and chemotherapy are also considered in this domain. Some steps of the pathway are indicated, as shown in different tumors. A: Ubiquitation in CCND1 levels is achievable by gamma irradiation [3]. B: Ubiquitin–proteasome system and autophagy functionally cooperate with one another for protein homeostasis [1]. C: Autophagy is induced in response to environmental stress resulting in abnormal or degraded proteins [5]. Beclin-1 (encoded by the BECN1 gene) is an autophagy protein, which has a critical role in the autophagy machinery. LC3 is a protein of the late autophagy pathway, necessary for autophagosome, biogenesis, and is used as an autophagy marker. D: Mammalian target of rapamycin (mTOR) inhibitors (everolimus [2], rapamycin [6,11], amiodarone [11]) activate autophagy, also concurrently with radiation or temozolomide chemotherapy [6]. E: The autophagosome engulfs degraded proteins [5], subsequently digested via its fusion with lysosomes. CCND1 colocalizes with Beclin-1 in the cytoplasm [7] after cancer therapy and this suggests its autophagy degradation. F and G: CCND1 degradation deactivates the formation of the CCND1/CDK4 and CDK6 complex, thus activating the Rb1-dependent onco-suppressive pathway [10] and hampering cell cycle progression [2,6]. In gray: an alternative pathway of CCND1 degradation is through the ubiquitin–proteasome mechanism (UPD). Active mTOR complex 1 (mTORC1) inhibits both UPD and autophagy (dashed lines). PI3K, phosphatidylinositol 3-kinase. Image copyright © 2021, The American Physiological Society [86].