The landscape of cyclin-dependent kinase 4/6 inhibitors in solid malignancies: emphasis on immunotherapy combinatorial strategies.

IF 3.5 4区 医学 Q2 ONCOLOGY
Sara A Hussein, Ahmed H Saadawy, Eman Badr, Maha R A Abdollah, Neamtullah Wael, Rasha M Allam, Ahmed M Al-Abd, Ana Maria Roncero Sanchez, Mai F Tolba
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Abstract

Given the pivotal role of CDK4/6 deregulation in the pathogenesis of various malignancies, CDK4/6 inhibitors have been incorporated into cancer treatment protocols. Beyond their antiproliferative effects, these inhibitors exhibit prominent immunomodulatory properties. Preclinical data indicated that CDK4/6 inhibitors enhance the tumor cell antigen presentation capacity and restrict the proliferation of immunosuppressive regulatory T-cells. Furthermore, studies showed that CDK4/6 inhibitors could enhance the development of memory T-cell in vivo in melanoma mouse models and in the clinical setting in breast cancer (BC) patients. In silico analysis identified 225 protein targets for CDK4/6 inhibitors involved in 57 immune-related pathways which further supported the immune-modulatory potential of these inhibitors in innate immunity, cytokine signaling, and adaptive immunity. Furthermore, 24 targets exhibited significantly higher protein expression in immune cell types compared to non-immune cell types, as indicated by data from the Human Protein Atlas. The favorable modulation of T-cell immunity by CDK4/6 inhibitors could complement the antitumor effect of immunotherapies, such as immune checkpoint inhibitors (ICIs), which hamper PD-1 /PD-L1 signaling and result in the reactivation of the antitumor T-cell response. Herein, we explore the clinical portfolio of CDK4/6 inhibitors across various solid malignancies, with emphasis on emerging combinations with ICIs.

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周期蛋白依赖性激酶4/6抑制剂在实体恶性肿瘤中的前景:强调免疫治疗组合策略。
鉴于CDK4/6在各种恶性肿瘤发病机制中的关键作用,CDK4/6抑制剂已被纳入癌症治疗方案。除了它们的抗增殖作用,这些抑制剂表现出突出的免疫调节特性。临床前数据表明,CDK4/6抑制剂增强肿瘤细胞抗原呈递能力,限制免疫抑制性调节性t细胞的增殖。此外,研究表明,CDK4/6抑制剂可以在黑色素瘤小鼠模型和乳腺癌(BC)患者的临床环境中促进记忆t细胞的发展。计算机分析鉴定了涉及57个免疫相关通路的CDK4/6抑制剂的225个蛋白靶点,进一步支持了这些抑制剂在先天免疫、细胞因子信号传导和适应性免疫中的免疫调节潜力。此外,人类蛋白质图谱的数据表明,与非免疫细胞类型相比,24个靶点在免疫细胞类型中表现出明显更高的蛋白质表达。CDK4/6抑制剂对t细胞免疫的有利调节可以补充免疫疗法的抗肿瘤作用,如免疫检查点抑制剂(ICIs),后者阻碍PD-1 /PD-L1信号传导并导致抗肿瘤t细胞应答的再激活。在此,我们探讨了CDK4/6抑制剂在各种实体恶性肿瘤中的临床组合,重点是与ICIs的新组合。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Medical Oncology
Medical Oncology 医学-肿瘤学
CiteScore
4.20
自引率
2.90%
发文量
259
审稿时长
1.4 months
期刊介绍: Medical Oncology (MO) communicates the results of clinical and experimental research in oncology and hematology, particularly experimental therapeutics within the fields of immunotherapy and chemotherapy. It also provides state-of-the-art reviews on clinical and experimental therapies. Topics covered include immunobiology, pathogenesis, and treatment of malignant tumors.
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