Activation of AR Sensitizes Breast Carcinomas to NVP-BEZ235's Therapeutic Effect Mediated by PTEN and KLLN Upregulation

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 þ /ER þ 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 þ

Androgen Receptor Inhibitor Enhances the Antitumor Effect of PARP Inhibitor in Breast Cancer Cells by Modulating DNA Damage Response

“…To fulfill this unmet need, some attempts have been made using AR inhibitors in combination with other targeted therapeutic agents, such as, aromatase inhibitor and NYP-BEZ235 (a PI3K and mTOR dual inhibitor; refs. [31][32][33]. However, these approaches are also limited in context-and subtype-specific cases.…”

Dactolisib (NVP-BEZ235) toxicity in murine brain tumour models

“…Of particular interest is the study of Wang et al, which reports that side effects during dactolisib-treatment of breast cancer bearing mice are reduced by the addition of dihydrotestosterone (DHT) [38]. The activation of androgen receptor (AR) by DHT is beneficial for breast cancer patients.…”

Targeting PI3K in cancer: mechanisms and advances in clinical trials

“…It is an imidazo [4,5-c] quinoline derivative compound that binds to the ATP-binding cleft of PI3K and mTOR kinase, inhibiting their catalytic activities [25]. BEZ235 exhibited satisfactory anticancer effects in preclinical studies in several types of cancer, including the following: triple-negative breast cancer, lung cancer, melanoma, colorectal cancer, renal cancer, prostate cancer, lymphoma, and mucinous adenocarcinoma of the ovary [73][74][75][76][77][78][79][80][81][82][83][84][85]. However, the clinical trials of BEZ235 were not satisfactory.…”