Journal
CANCER CELL
Volume 29, Issue 3, Pages 255-269Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2016.02.006
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Funding
- NIH [P50 CA168504, CA172461, U01CA180980, R01 CA083688, P01 CA080111]
- Susan G. Komen grant [SAC 10005]
- Breast Cancer Research Foundation
- Institutional Research Grant of Hollings Cancer Center
- Medical University of South Carolina
- National Health and Medical Research Council of Australia
- Eli Lilly
- Genentech
- AstraZeneca
- Acetylon
- Gilead Pharmaceuticals
- Novartis
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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.
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