Cancer Cell
Volume 29, Issue 3, 14 March 2016, Pages 255-269
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Article
Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors

https://doi.org/10.1016/j.ccell.2016.02.006Get rights and content
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Highlights

  • Cyclin D1/CDK4 mediate resistance to HER2 blockade in HER2+ breast cancer

  • CDK4/6 inhibition suppresses mTORC1, relieving inhibition of EGFR family kinases

  • Combined CDK4/6 and HER2 inhibition is effective in transgenic and PDX mouse models

  • CDK4/6 inhibitors delay tumor recurrence in a transgenic HER2+ breast cancer model

Summary

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.

Cited by (0)

16

Present address: Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA

17

Present address: Curis, Inc., Lexington, MA 02421, USA

18

Co-senior author