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Cancer Cell. 2016 Mar 14;29(3):255-269. doi: 10.1016/j.ccell.2016.02.006.

Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: shom_goel@dfci.harvard.edu.
2
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
3
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
4
Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
5
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, MA 02215, USA; Center for Functional Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
6
Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA 02115, USA; Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
7
Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, MA 02115, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
8
Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA.
9
Department of Pathology, Yale University, New Haven, CT 06520, USA.
10
Case Western Reserve School of Medicine, Cleveland, OH 44106, USA.
11
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
12
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: jean_zhao@dfci.harvard.edu.

Abstract

Using transgenic mouse models, cell line-based functional studies, and clinical specimens, we show that cyclin D1/CDK4 mediate resistance to targeted therapy for HER2-positive breast cancer. This is overcome using CDK4/6 inhibitors. Inhibition of CDK4/6 not only suppresses Rb phosphorylation, but also reduces TSC2 phosphorylation and thus partially attenuates mTORC1 activity. This relieves feedback inhibition of upstream EGFR family kinases, resensitizing tumors to EGFR/HER2 blockade. Consequently, dual inhibition of EGFR/HER2 and CDK4/6 invokes a more potent suppression of TSC2 phosphorylation and hence mTORC1/S6K/S6RP activity. The suppression of both Rb and S6RP enhances G1 arrest and a phenotype resembling cellular senescence. In vivo, CDK4/6 inhibitors sensitize patient-derived xenograft tumors to HER2-targeted therapies and delay tumor recurrence in a transgenic model of HER2-positive breast cancer.

PMID:
26977878
PMCID:
PMC4794996
DOI:
10.1016/j.ccell.2016.02.006
[Indexed for MEDLINE]
Free PMC Article

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