Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors
Shom Goel, Qi Wang, April C Watt, Sara M Tolaney, Deborah A Dillon, Wei Li, Susanne Ramm, Adam C Palmer, Haluk Yuzugullu, Vinay Varadan, David Tuck, Lyndsay N Harris, Kwok-Kin Wong, X Shirley Liu, Piotr Sicinski, Eric P Winer, Ian E Krop, Jean J Zhao, Shom Goel, Qi Wang, April C Watt, Sara M Tolaney, Deborah A Dillon, Wei Li, Susanne Ramm, Adam C Palmer, Haluk Yuzugullu, Vinay Varadan, David Tuck, Lyndsay N Harris, Kwok-Kin Wong, X Shirley Liu, Piotr Sicinski, Eric P Winer, Ian E Krop, Jean J Zhao
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.
Conflict of interest statement
Conflicts of interest
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.
Copyright © 2016 Elsevier Inc. All rights reserved.
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Source: PubMed