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

Cancer Cell. 2016 Mar 14;29(3):255-269. 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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 4 / metabolism
  • Cyclin-Dependent Kinase 6 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 6 / metabolism
  • Disease Models, Animal
  • Drug Resistance, Neoplasm / drug effects*
  • ErbB Receptors / metabolism
  • Female
  • Humans
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Nude
  • Mice, Transgenic
  • Multiprotein Complexes / metabolism
  • Neoplasm Recurrence, Local / mortality
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology*
  • Receptor, ErbB-2 / metabolism*
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Suppressor Proteins / metabolism

Substances

  • Multiprotein Complexes
  • Protein Kinase Inhibitors
  • Tumor Suppressor Proteins
  • TOR Serine-Threonine Kinases
  • ErbB Receptors
  • Receptor, ErbB-2
  • Mechanistic Target of Rapamycin Complex 1
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6