ErbB2 signaling appears to be increased and may enhance AR activity in a subset of CRPC, but agents targeting ErbB2 have not been effective. This study was undertaken to assess ErbB2 activity in abiraterone-resistant prostate cancer (PCa), and determine whether it may contribute to androgen receptor (AR) signaling in these tumors.
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AR activity and ErbB2 signaling were examined in the radical prostatectomy specimens from a neoadjuvant clinical trial of leuprolide plus abiraterone, and in the specimens from abiraterone-resistant CRPC xenograft models. The effect of ErbB2 signaling on AR activity was determined in two CRPC cell lines. Moreover, the effect of combination treatment with abiraterone and an ErbB2 inhibitor was assessed in a CRPC xenograft model.
We found that ErbB2 signaling was elevated in residual tumor following abiraterone treatment in a subset of patients, and was associated with higher nuclear AR expression. In xenograft models, we similarly demonstrated that ErbB2 signaling was increased and associated with AR reactivation in abiraterone-resistant tumors. Mechanistically, we show that ErbB2 signaling and subsequent activation of the PI3K/AKT signaling stabilizes AR protein. Furthermore, concomitantly treating CRPC cells with abiraterone and an ErbB2 inhibitor, lapatinib, blocked AR reactivation and suppressed tumor progression.
ErbB2 signaling is elevated in a subset of abiraterone-resistant prostate cancer patients and stabilizes AR protein. Combination therapy with abiraterone and ErbB2 antagonists may be effective for treating the subset of CRPC with elevated ErbB2 activity.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2016 Mar 02 [Epub ahead of print]
Shuai Gao, Huihui Ye, Sean Gerrin, Hongyun Wang, Ankur Sharma, Sen Chen, Akash Patnaik, Adam G Sowalsky, Olga Voznesensky, Wanting Han, Ziyang Yu, Elahe Mostaghel, Peter S Nelson, Mary-Ellen Taplin, Steven P Balk, Changmeng Cai
Center for Personalized Cancer Therapy, University of Massachusetts Boston., Pathology, Beth Israel Deaconess Medical Center., Hematology-Oncology Division, Beth Israel Deaconess Medical Center., Medicine, BIDMC., Department of Cancer Biology, Thomas Jefferson University., Medicine, Beth Israel Deaconess Medical Center., Medicine-Hematology/Oncology, University of Chicago., Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute., Medicine, Beth Israel Deaconess Medical Center., Center for Personalized Cancer Therapy, University of Massachusetts Boston., Hematology-Oncology Division, Beth Israel Deaconess Medical Center., Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center., Division of Human Biology, Fred Hutchinson Cancer Research Center., Dana-Farber Cancer Institute., Division of Hematology and Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School., Center for Personalized Cancer Therapy, University of Massachusetts Boston