CDK4/6 and autophagy inhibitors synergistically induce senescence in

 Rb positive cytoplasmic cyclin E negative cancers

Smruthi Vijayaraghavan, Cansu Karakas, Iman Doostan, Xian Chen, Tuyen Bui, Min Yi, et al.

Nat Commun.2017 Jun 27;8:15916

Speaker: Wan-Yu Lee (李婉瑜)                            Time: 13:00~14:00, Sep, 27th, 2017

Commentator: Dr. Li-Jin Hsu (徐麗君老師)     Place: Room 601

Abstract:

Deregulation of the cell cycle checkpoint proteins is a key hallmark of cancer, resulting in uncontrolled cellular proliferation and tumorigenesis.¹ Cyclin D-dependent kinases CDK4 and CDK6 which serve as positive regulators of cell cycle are overactive in the majority of human cancers. Selective CDK4/6 inhibitors have shown promising preclinical and clinical activities in numerous solid tumors. In particular, the CDK4/6 inhibitor palbociclib (Ibrance) has shown benefits in Phase II and III clinical trials in advanced estrogen receptor-positive (ER+) breast cancers, doubling the progression-free survival (PFS) compared to classical endocrine treatment.² However, it still remains some limitations for the treatment. Adverse events such as neutropenia and leukopenia lead to discontinuation of treatment. Some ER (+) cancer patients do not respond to palbociclib or develop clinical resistance with disease progression. Lack of reliable biomarkers as prognostic indicators for advanced ER (+) breast cancer treated with palbociclib is also an important issue. Here, the authors proposed the biomarker-driven approach that can enhance the efficacy of palbociclib in breast cancer. They first found that breast cancer cells activate ROS-mediated senescence and autophagy in response to palbociclib, and the combination of autophagy inhibitor and palbociclib induces irreversible growth inhibition and enhanced senescence in vitro, showing that autophagy protect ER(+) breast cancer cells from palbociclib-induced senescence. By using patient-derived xenograft tumor mouse model, they demonstrated that autophagy inhibition synergizes with palbociclib can also induce irreversible tumor growth inhibition in vivo. Furthermore, they provided evidences to show that intact G1/S transition with Rb-positive and low-molecular-weight isoform of cyclin E –negative is a reliable prognostic biomarker in ER (+) breast cancer patients, and predictive of preclinical sensitivity to this drug combination. In addition to ER (+) breast cancer, combination of palbociclib and autophagy inhibitors can also be used to treat triple-negative breast cancer (TNBC) and other solid cancers those have intact G1/S checkpoint. These findings provide a novel and promising biomarker-driven combination therapeutic strategy to treat breast and other solid tumors.

References:

1.      Sandhu C, Slingerland J. Deregulation of the cell cycle in cancer. Cancer Detect Prev. 24(2):107-18 (2000)

2.      Turner, N. C. et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 373, 209–219 (2015).