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

S Goel; Q Wang; AC Watt; SM Tolaney; DA Dillon; W Li; S Ramm; AC Palmer; H Yuzugullu; V Varadan; D Tuck; LN Harris; KK Wong; XS Liu; P Sicinski; EP Winer; IE Krop; JJ Zhao

Journal article

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

S Goel, Q Wang, AC Watt, SM Tolaney, DA Dillon, W Li, S Ramm, AC Palmer, H Yuzugullu, V Varadan, D Tuck, LN Harris, KK Wong, XS Liu, P Sicinski, EP Winer, IE Krop, JJ Zhao

Cancer Cell | CELL PRESS | Published : 2016

DOI: 10.1016/j.ccell.2016.02.006

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 p..

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University of Melbourne Researchers

Shom Goel Author

April Watt Author

Susanne Ramm Author

Grants

Awarded by National Institutes of Health

Funding Acknowledgements

A.C.W. and Q.W. contributed equally to this work. We thank Dr Roderick Bronson from the Rodent Histopathology Core Facility at Harvard Medical School (HMS) for helpful discussions regarding mouse pathology, and Dr Peter Sorger from the Department of Systems Biology at HMS for his advice and support. We also thank Mayuko Segawa for technical assistance. We thank Neil O'Brien (UCLA) for the gift of trastuzumab-resistant BT474 and SKBR3 cell lines. This study was supported by NIH P50 CA168504 (to E.P.W.) and CA172461 (to J.J.Z.), a Susan G. Komen grant SAC 10005 (to I.E.K.), the Breast Cancer Research Foundation (to E.P.W. and J.J.Z.), and Aid for Cancer Research (to E.P.W.). Q.W. is supported by the Institutional Research Grant of Hollings Cancer Center and the Medical University of South Carolina. W.L. and X.S.L. are supported by NIH grant U01CA180980. A.C.P. is supported by the National Health and Medical Research Council of Australia. P.S. is supported by NIH grants R01 CA083688 and P01 CA080111. S.G. conducts research sponsored by Eli Lilly. S.T. receives research funding from Genentech. K.K.W conducts research sponsored by AstraZeneca, Acetylon, and Gilead Pharmaceuticals, performs consultancy for G1 Therapeutics and Array Therapeutics, and is a founder and equity holder of G1 Therapeutics. P.S. receives research funding and serves as a consultant for Novartis.