CDK4/6 inhibitors: a novel strategy for tumor radiosensitization

Abstract

Recently, the focus of enhancing tumor radiosensitivity has shifted from chemotherapeutics to targeted therapies. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are a novel class of selective cell cycle therapeutics that target the cyclin D-CDK4/6 complex and induce G1 phase arrest. These agents have demonstrated favorable effects when used as monotherapy or combined with endocrine therapy and targeted inhibitors, stimulating further explorations of other combination strategies. Multiple preclinical studies have indicated that CDK4/6 inhibitors exhibit a synergistic effect with radiotherapy both in vitro and in vivo. The principal mechanisms of radiosensitization effects include inhibition of DNA damage repair, enhancement of apoptosis, and blockade of cell cycle progression, which provide the rationale for clinical use. CDK4/6 inhibitors also induce cellular senescence and promote anti-tumor immunity, which might represent potential mechanisms for radiosensitization. Several small sample clinical studies have preliminarily indicated that the combination of CDK4/6 inhibitors and radiotherapy exhibited well-tolerated toxicity and promising efficacy. However, most clinical trials in combined therapy remain in the recruitment stage. Further work is required to seek optimal radiotherapy-drug combinations. In this review, we describe the effects and underlying mechanisms of CDK4/6 inhibitors as a radiosensitizer and discuss previous clinical studies to evaluate the prospects and challenges of this combination.

Mechanisms and Implications of CDK4/6 Inhibitors for the Treatment of NSCLC

“…Multiple preclinical and small sample clinical studies showed that CDK4/6 inhibitors exhibit a collaborative effect during radiotherapy in vitro and in vivo and show well-tolerated toxicity and promising efficacy in patients (44)(45)(46)(47). The potential mechanisms of clinical radiosensitization effects might be apoptosis enhancement, cell cycle progression blockage, and induction of cellular senescence and antitumor immunity (48). A preclinical study showed that abemaciclib and ionizing radiation (IR) had a good radiosensitization effect on tumor cells in proliferative and plateau-phase and tumor xenografts, but had little radiosensitization effect on normal cells, and improve the radiation sensitivity of NSCLC in vitro and in vivo.…”

The role of CDK4/6 inhibitors in early breast cancer

“…The combination of CDK4/6i and RT has been considered of risk as it may exacerbate known CDK4/6i toxicities, particularly neutropenia and leukopenia. However, preclinical data indicate that CDK4/6i may enhance the therapeutic effects of RT [54,55].…”

“…The combination of CDK4/6i and RT has been considered of risk as it may exacerbate known CDK4/6i toxicities, particularly neutropenia and leukopenia. However, pre-clinical data indicate that CDK4/6i may enhance the therapeutic effects of RT [ 54 , 55 ]. Specifically, palbociclib may act as an inhibitor of double-stranded DNA repair [ 56 ], and abemaciclib as a multi-functional radiation modifier [ 57 ].…”

Targeting PI3K, FGFR, CDK4/6 Signaling Pathways Together With Cytostatics and Radiotherapy in Two Medulloblastoma Cell Lines

“…For the doseeffect-based median-effect principle, a CI<0.7 indicates synergism, a 0.7<CI>1.45 indicates an additive effect, while a CI>1. 45 indicates an antagonistic effect. The WST-1 assays were also complemented with assessment of cell confluence, cytotoxicity, and apoptosis using the IncuCyte S3 Live−Cell Analysis System, and the data extrapolated from these assays are presented below.…”