Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Boulevard, Houston, Texas 77030, USA.
Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, 6767 Bertner Avenue, Houston, Texas 77030, USA.
Nat Commun. 2017 Jun 27;8:15916. doi: 10.1038/ncomms15916.
Deregulation of the cell cycle machinery is a hallmark of cancer. While CDK4/6 inhibitors are FDA approved (palbociclib) for treating advanced estrogen receptor-positive breast cancer, two major clinical challenges remain: (i) adverse events leading to therapy discontinuation and (ii) lack of reliable biomarkers. Here we report that breast cancer cells activate autophagy in response to palbociclib, and that the combination of autophagy and CDK4/6 inhibitors induces irreversible growth inhibition and senescence in vitro, and diminishes growth of cell line and patient-derived xenograft tumours in vivo. Furthermore, intact G1/S transition (Rb-positive and low-molecular-weight isoform of cyclin E (cytoplasmic)-negative) is a reliable prognostic biomarker in ER positive breast cancer patients, and predictive of preclinical sensitivity to this drug combination. Inhibition of CDK4/6 and autophagy is also synergistic in other solid cancers with an intact G1/S checkpoint, providing a novel and promising biomarker-driven combination therapeutic strategy to treat breast and other solid tumours.
细胞周期调控机制失调是癌症的一个标志。虽然 CDK4/6 抑制剂（帕博西利）已获 FDA 批准用于治疗晚期雌激素受体阳性乳腺癌，但仍存在两个主要的临床挑战：（i）导致治疗中断的不良反应，（ii）缺乏可靠的生物标志物。本研究报告称，乳腺癌细胞对帕博西利产生自噬反应，自噬与 CDK4/6 抑制剂的联合使用可在体外诱导不可逆的生长抑制和衰老，并在体内减少细胞系和患者来源的异种移植瘤的生长。此外，完整的 G1/S 期转变（Rb 阳性和低分子量细胞周期蛋白 E 同工型（细胞质）阴性）是 ER 阳性乳腺癌患者的可靠预后生物标志物，预测对这种药物组合的临床前敏感性。在其他具有完整 G1/S 检查点的实体瘤中，抑制 CDK4/6 和自噬也具有协同作用，为治疗乳腺癌和其他实体瘤提供了一种新颖而有前途的基于生物标志物的联合治疗策略。
