Background:Prostate cancer (PCa) contributes to almost 15% of US cancer cases annually with significant racial disparities, where black men are more likely to develop and die from prostate cancer than any other cohort. Previously, we reported that HER3/ERBB3 overexpression (OE) was enriched in the tumors of Black/ African American patients and was correlated with a unique androgen receptor signature as well as worse clinical outcomes. Here, we evaluate an expanded and more mature patient cohort to understand the effect of HER3 OE on clinical outcomes. In vitro experiments further support the targeting of HER3 in prostate cancer disease.
Methods:Chart review was performed on a diverse cohort of PCa patients from the University of Illinois Health (n=106). Tempus laboratories performed whole transcriptome RNA sequencing, and HER3/ERBB3 OE status was determined by Tempus as compared to a reference database. Patients were grouped into HER3 OE and wild-type groups, and clinical outcomes were analyzed between groups using students’ t-test and Kaplan Meier plots with the Gehan-Breslow-Wilcoxon test. LNCaP cells were virally transduced with HER3 overexpression and non-targeting control vectors and validated via Western blot. Cell growth was quantified via nuclear fluorescence object count using Incucyte instruments and software. Drug treatment efficacy was validated via Western blot.
Results:The final cohort (n= 71 Black/AA, 19 white, and 5 other) demonstrated 42% of patients presenting with HER3 OE. A majority of patients presented with de novo metastases (55% of HER3 OE, 45% of HER3 WT). Of patients who initially presented with localized disease, time to metastasis was significantly faster in the HER3 OE group (p=0.04). HER3 OE was also associated with faster time to the development of castration resistance (p=0.02). In preclinical PCa models, HER3 OE cells grew significantly faster than control(p≤0.01), and were less sensitive to enzalutamide(p≤0.01). Additionally, we found that by inhibiting HER3 signaling (patritumab, erlotinib, trastuzumab, capivasertib) PCa cells become more sensitized to enzalutamide(p≤0.01), suggesting a role for dual AR and HER3 targeting in PCa treatment.
Conclusions:Our clinical and translational data supports the role of HER3 overexpression as a novel and targetable prognostic marker in diverse patients with PCa. Future studies should further evaluate HER3 inhibition in combination with AR targeted therapies to improve therapy sensitivity and reduce development of resistant disease.
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