title: 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(+)/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.
authors.affiliation: Corresponding Author: Charis Eng, Cleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, OH 44195. engc@ccf.org.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Qi
authors.initials: Q
authors.lastname: Yu
authors.forename: Xin
authors.initials: X
authors.lastname: He
authors.forename: Todd
authors.initials: T
authors.lastname: Romigh
authors.forename: Jessica
authors.initials: J
authors.lastname: Altemus
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D013196:Dihydrotestosterone / Q000008:administration & dosage / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D061986:MCF-7 Cells; D008819:Mice, Nude; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D011804:Quinolines / Q000008:administration & dosage / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D007093:Imidazoles; C554482:KLLN protein, human; D011804:Quinolines; D011944:Receptors, Androgen; D025521:Tumor Suppressor Proteins; D013196:Dihydrotestosterone; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C531198:dactolisib