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Nat Commun. 2017 Jun 27;8:15916. doi: 10.1038/ncomms15916.

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

Author information

1
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, 6565 MD Anderson Boulevard, Houston, Texas 77030, USA.
2
Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, 6767 Bertner Avenue, Houston, Texas 77030, USA.
3
Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Houston, Texas 77030, USA.
4
Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, 1155 Pressler Street, Houston, Texas 77030, USA.
5
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.
6
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
7
Division of Hematology Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

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.

PMID:
28653662
PMCID:
PMC5490269
DOI:
10.1038/ncomms15916
[Indexed for MEDLINE]
Free PMC Article

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