Abstract B021: Examining the role of HER2 signaling in promoting prostate cancer proliferation in an androgen receptor-low environment
Authors: Wilkinson Scott , Ku Anson , King Isaiah , Baj Anna , Low Daniel , Ye Huihui , Harmon Stephanie A. , Terrigino Nicholas T. , Bright John R. , Atway Rayann , Trostel Shana Y. , Lis Rosina T. , Turkbey Baris , Dahut William L. , Karzai Fatima , Sowalsky Adam G. 
Published: June 2023

Abstract
Background: Intense neoadjuvant androgen deprivation therapy (inADT) reduces prostate cancer recurrence in approximately 40% of patients with intermediate/high risk prostate cancer. Using samples from our recent phase 2 study (NCT02430480) from patients undergoing 6 months of inADT prior to radical prostatectomy, we sought to examine molecular features present at baseline that correlate with pathologic response following surgery. Methods: Tumors from 37 patients with locally advanced prostate cancer were subjected to immunohistochemistry (IHC) and laser capture microdissection to obtain 143 histologically distinct foci. RNA was isolated from each focus and used to generate RNA-seq libraries. Differentially-expressed genes were determined per-unit of residual tumor volume using linear mixed-effect models. Histologic features and staining intensities were obtained from IHC of posttreatment specimens. Ingenuity Pathway Analysis (IPA) identified upstream regulators at baseline that interacted with pathologic outcome. Cancer cell lines were treated with a panel of EGFR family inhibitors and androgen receptor (AR) axis inhibitors. Protein and RNA expression were measured to identify the impact of dual inhibition. Results: In pre-treatment targeted biopsies from men with locally advanced prostate cancer, we observed that tumor samples that exhibited worse response to inADT had lower AR activity at baseline, presumably due to a decreased dependency on AR, potentially related to increased dependency on alternative growth pathways. These incomplete/nonresponding tumors displayed a significant increase in expression of EFGR family signaling (EGFR, HER2, and HER3) using IPA, which have previously been shown to serve as bypass mechanisms to AR signaling to drive downstream PI3K activity. HER2 was the most abundantly expressed protein by IHC in posttreatment tumors. Given the multitude of receptor tyrosine kinases (RTKs) regulated by EGFR family signaling and RTK inhibitors targeting this activity, we examined the impact of combining RTK inhibitors with ADT to overcome resistance to ADT. Afatinib, lapatinib, and neratinib showed the greatest anti-tumor efficacy in vitro. Treatment with these agents rapidly and dynamically increased AR expression and activity. We observed synergistic effects on cell viability and proliferation by treating cell lines with combination therapy of antiandrogen therapy and these inhibitors. Conclusions: Our data suggest that elevated HER2 activity defines an AR-low subtype of prostate cancer that is resistant to inADT. Disrupting the HER2-mediated bypass of AR blockade re-sensitized resistant PC cells to AR-targeted therapy. These effects were observed in an untreated setting and represent a divergent path in tumorigenesis where prostate tumors develop with intrinsically lower AR activity. These findings will be validated using genetic abrogation of HER2 in additional clinical samples, organoids, and patient-derived xenograft models, and represent new opportunities for combination therapy in newly-diagnosed high-risk disease.
Citation Format: Scott Wilkinson, Anson Ku, Isaiah King, Anna Baj, Daniel Low, Huihui Ye, Stephanie A. Harmon, Nicholas T. Terrigino, John R. Bright, Rayann Atway, Shana Y. Trostel, Rosina T. Lis, Baris Turkbey, William L. Dahut, Fatima Karzai, Adam G. Sowalsky. Examining the role of HER2 signaling in promoting prostate cancer proliferation in an androgen receptor-low environment [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B021.