CDK4/6 inhibitors: a novel strategy for tumor radiosensitization
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(2020) 39:188
REVIEW
Open Access
CDK4/6 inhibitors: a novel strategy for tumor radiosensitization Yilan Yang1,2†, Jurui Luo1,2†, Xingxing Chen1,2, Zhaozhi Yang1,2, Xin Mei1,2, Jinli Ma1,2, Zhen Zhang1,2, Xiaomao Guo1,2* and Xiaoli Yu1,2*
Abstract Recently, the focus of enhancing tumor radiosensitivity has shifted from chemotherapeutics to targeted therapies. Cyclindependent kinase 4 and 6 (CDK4/6) inhibitors are a novel class of selective cell cycle therapeutics that target the cyclin DCDK4/6 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. Keywords: CDK4/6 inhibitor, Radiotherapy, Radiosensitivity
Background Radiotherapy is one of the most important local control methods of malignant tumors. Approximately 50% of cancer patients receive radiotherapy during the treatment process [1]. However, the radioresistance of tumor cells limits the ability to reach a curative dose of radiation, which reduces radiotherapy efficacy and is more likely to cause local failures [1, 2]. Substantial efforts have been made to improve the radiosensitivity via various types of radiation modulators. The early-stage radiosensitizers are mostly chemotherapeutic agents, such as cisplatin and 5fluorouracil, which have been demonstrated to enhance * Correspondence: [email protected]; [email protected] † Yilan Yang and Jurui Luo contributed equally to this work. 1 Department of Radiation Oncology, Fudan University Shanghai Cancer Center, 270 DongAn Road, Shanghai 200032, China Full list of author information is available at the end of the article
radiosensitivity in head and neck squamous cell carcinoma (HNSCC), nasopharyngeal carcinoma (NPC), and gastrointestinal cancers [3]. These chemotherapeutics exhibit radiosensitization effects by increasing radiation damage and inhibiting DNA repair process [4, 5]. However, due to
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