• FDA批准CDK4/6抑制剂palbociclib治疗晚期雌激素受体阳性乳腺癌,临床上的不足之处包括不良事件导致治疗中断和缺乏可靠的生物标志物;
  • Palbociclib发挥作用时,乳腺癌细胞激活自噬作用,联合自噬与CDK4/6抑制剂,在体外诱导不可逆生长抑制和老化,在体内减缓细胞株和患者来源移植瘤的生长;
  • 完整的G1/S转换(Rb阳性、胞浆型细胞周期素E低分子量同功酶阴性)是ER阳性乳腺癌患者的可靠的预后性生物标志物,预测联合用药的临床前敏感性。

CDK4/6 and autophagy inhibitors synergistically induce senescence in Rb positive cytoplasmic cyclin E negative cancers



2017-06-27, Article

Abstract & Authors:展开

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.

First Authors:
Smruthi Vijayaraghavan

Correspondence Authors:
Khandan Keyomarsi

All Authors:
Smruthi Vijayaraghavan,Cansu Karakas,Iman Doostan,Xian Chen,Tuyen Bui,Min Yi,Akshara S Raghavendra,Yang Zhao,Sami I Bashour,Nuhad K Ibrahim,Meghan Karuturi,Jing Wang,Jeffrey D Winkler,Ravi K Amaravadi,Kelly K Hunt,Debu Tripathy,Khandan Keyomarsi