Abstract 395: Aberrant HER2 signaling is a therapeutic target in a subset of castration-resistant prostate cancer

Background: Aberrant HER2 signaling promotes androgen receptor activity and is associated with 18-25% of castration-resistant prostate cancer (CRPC). We present preclinical and clinical data supporting signaling by canonical HER3/HER2 interaction and a constitutively active splice variant of HER2 (d16HER2) as potential oncogenic drivers of CRPC. Further, we provide preclinical evidence that increased HER2 signaling may be targeted with irreversible HER2-targeted tyrosine kinase inhibitors (TKIs) to block tumor growth. Methods: Human-derived VCaP prostate cancer xenografts were serially biopsied prior to castration, at castration-resistance, and after resistance to abiraterone + enzalutamide (Abi/Enza). Biopsies were submitted for RNA sequencing and RT-PCR, immunohistochemistry (IHC), and reverse-phase protein array (RPPA) for validation of gene/protein expression changes. Castration-resistant VCaP and LuCaP-70CR xenografts were treated with reversible EGFR/HER2 TKI lapatinib (100 mg/kg) or irreversible pan-HER TKIs afatinib (20 mg/kg) or neratinib (20 mg/kg). Transcript levels of total HER2 and d16HER2 variant were determined for TCGA and SU2C prostate cancer (PCa) datasets. IHC for phospho-HER2 (Tyr1221/1222) and phospho-HER3 (Tyr1289) were performed on tumor samples from 49 heavily-treated metastatic CRPC (mCRPC) patients and compared to 18 hormone-naive prostatectomy samples. Results: VCaP xenografts exhibit increased activation of HER3/HER2 signaling and increased expression of d16HER2 with progression through castration and Abi/Enza therapy. Increases in pHER2 and pHER3 were observed by IHC and RPPA in serial biopsies of individual tumors, and increases in total HER2, wtHER2, and d16HER2 transcripts were observed by RT-PCR. Castration-resistant VCaP and LuCaP-70CR xenografts rapidly become resistant to lapatinib within 5 days, while the irreversible pan-HER TKIs inhibited tumor growth for at least 15 days. Analysis of TCGA (mostly hormone-naive PCa) and SU2C (mCRPC) RNAseq datasets shows enrichment of tumors expressing d16HER2 in mCRPC. pHER3/pHER2 IHC in patient tumor specimens showed 9/49 (18%) mCRPC tumors exhibited concurrent pHER3/pHER2 staining compared to 1/18 (6%) of hormone-naive PCa. An additional 4/49 (8%) mCRPC tumors stained positive for pHER2 alone, possibly representing d16HER2 activity. Conclusions: HER2 overexpression and d16HER2 expression are associated with PCa progression, castration-resistance, and resistance to second-line hormonal therapy. HER2-targeted therapy with irreversible TKIs is more effective at inhibiting CRPC growth than the reversible TKI lapatinib. Our data indicate a subset of CRPC with aberrant HER2 signaling may be clinically actionable, and further studies to investigate potential treatment with an irreversible pan-HER TKI such as neratinib in biomarker-selected metastatic CRPC patients is warranted. Citation Format: Joshua W. Russo, Xin Gao, David J. Einstein, Glenn J. Bubley, Steven P. Balk. Aberrant HER2 signaling is a therapeutic target in a subset of castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 395.