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

Publication date: 14 March 2016
Source:Cancer Cell, Volume 29, Issue 3
Author(s): 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
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.

Teaser

Goel et al. show that cyclin D1/CDK4 mediate targeted therapy resistance in HER2⁺ breast cancer. CDK4/6 inhibition overcomes this resistance by increasing tumor cell dependence on EGFR family kinase signaling. CDK4/6 inhibitors resensitize PDX tumors to HER2-targeted therapies and delay tumor recurrence in vivo.


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