Activation of AR sensitizes breast carcinomas to NVP-BEZ235's therapeutic effect mediated by PTEN and KLLN upregulation

Mol Cancer Ther. 2014 Feb;13(2):517-27. doi: 10.1158/1535-7163.MCT-13-0655. Epub 2013 Dec 19.

Abstract

NVP-BEZ235 is a newly developed dual PI3K/mTOR inhibitor, being tested in multiple clinical trials, including breast cancer. NVP-BEZ235 selectively induces cell growth inhibition in a subset, but not all, breast cancer cell lines. However, it remains a challenge to distinguish between sensitive and resistant tumors, particularly in the pretreatment setting. Here, we used ten breast cancer cell lines to compare NVP-BEZ235 sensitivity and in the context of androgen receptor (AR) activation during NVP-BEZ235 treatment. We also used female SCID mice bearing breast tumor xenografts to investigate the beneficial effect of dihydrotestosterone/NVP-BEZ235 combination treatment compared with each alone. We found that AR-positive breast cancer cell lines are much more sensitive to NVP-BEZ235 compared with AR-negative cells, regardless of PTEN or PI3KCA status. Reintroducing AR expression in NVP-BEZ235 nonresponsive AR-negative cells restored the response. DHT/NVP-BEZ235 combination not only resulted in a more significant growth inhibition than either drug alone, but also achieved tumor regression and complete responses for AR(+)/ER(+) tumors. This beneficial effect was mediated by dihydrotestosterone (DHT)-induced PTEN and KLLN expression. Furthermore, DHT could also reverse NVP-BEZ235-induced side effects such as skin rash and weight loss. Our data suggest that AR expression may be an independent predictive biomarker for response to NVP-BEZ235. AR induction could add benefit during NVP-BEZ235 treatment in patients, especially with AR(+)/ER(+) breast carcinomas.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Apoptosis / drug effects
  • Blotting, Western
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Dihydrotestosterone / administration & dosage
  • Dihydrotestosterone / pharmacology
  • Drug Synergism
  • Female
  • Humans
  • Imidazoles / administration & dosage
  • Imidazoles / pharmacology*
  • MCF-7 Cells
  • Mice, Nude
  • PTEN Phosphohydrolase / metabolism*
  • Quinolines / administration & dosage
  • Quinolines / pharmacology*
  • Receptors, Androgen / genetics
  • Receptors, Androgen / metabolism*
  • Time Factors
  • Tumor Suppressor Proteins / metabolism*
  • Up-Regulation / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • AR protein, human
  • Imidazoles
  • KLLN protein, human
  • Quinolines
  • Receptors, Androgen
  • Tumor Suppressor Proteins
  • Dihydrotestosterone
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • dactolisib