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, 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 and Khandan Keyomarsi ()
Additional contact information
Smruthi Vijayaraghavan: The University of Texas MD Anderson Cancer Center
Cansu Karakas: The University of Texas MD Anderson Cancer Center
Iman Doostan: The University of Texas MD Anderson Cancer Center
Xian Chen: The University of Texas MD Anderson Cancer Center
Tuyen Bui: The University of Texas MD Anderson Cancer Center
Min Yi: The University of Texas MD Anderson Cancer Center
Akshara S. Raghavendra: The University of Texas MD Anderson Cancer Center
Yang Zhao: The University of Texas MD Anderson Cancer Center
Sami I. Bashour: The University of Texas MD Anderson Cancer Center
Nuhad K. Ibrahim: The University of Texas MD Anderson Cancer Center
Meghan Karuturi: The University of Texas MD Anderson Cancer Center
Jing Wang: The University of Texas MD Anderson Cancer Center
Jeffrey D. Winkler: University of Pennsylvania
Ravi K. Amaravadi: Perelman School of Medicine, University of Pennsylvania
Kelly K. Hunt: The University of Texas MD Anderson Cancer Center
Debu Tripathy: The University of Texas MD Anderson Cancer Center
Khandan Keyomarsi: The University of Texas MD Anderson Cancer Center

Nature Communications, 2017, vol. 8, issue 1, 1-17

Abstract: Abstract 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.

Date: 2017
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/ncomms15916 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15916

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms15916

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().