Identification of asporin as a HER3 ligand exposes a therapeutic vulnerability in prostate cancer
Amanda B. Hesterberg, Hong Yuen Wong, Jorgen Jackson, Monika Antunovic, Brenda L. Rios, Evan Watkins, Riley E. Bergman, Brad A. Davidson, Sarah E. Ginther, Diana Graves, Elliott F. Nahmias, Jared A. Googel, Lillian B. Martin, Violeta Sanchez, Paula I. Gonzalez-Ericsson, Quanhu Sheng, Benjamin P. Brown, Jens Meiler, Kerry R. Schaffer, Jennifer B. Gordetsky, Ben H. Park, Paula J. Hurley
Amanda B. Hesterberg, Hong Yuen Wong, Jorgen Jackson, Monika Antunovic, Brenda L. Rios, Evan Watkins, Riley E. Bergman, Brad A. Davidson, Sarah E. Ginther, Diana Graves, Elliott F. Nahmias, Jared A. Googel, Lillian B. Martin, Violeta Sanchez, Paula I. Gonzalez-Ericsson, Quanhu Sheng, Benjamin P. Brown, Jens Meiler, Kerry R. Schaffer, Jennifer B. Gordetsky, Ben H. Park, Paula J. Hurley
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Research Article Cell biology Oncology

Identification of asporin as a HER3 ligand exposes a therapeutic vulnerability in prostate cancer

Abstract

Cancer-associated fibroblasts (CAFs) are part of the tumor microenvironment (TME) that enable cancer cells to establish metastases, but the mechanisms of these interactions are not fully known. Herein, we identified a paracrine mechanism in which CAF-secreted asporin (ASPN) activated ErbB signaling and subsequent migration of adjacent prostate cancer cells. Our data support that ASPN bound directly to the ligand binding domain of human epidermal growth factor 3 (HER3) and induced HER2/HER3 heterodimerization and activation of the PI3K, MAPK, and calcium pathways. Genetic and therapeutic inhibition of HER2/HER3 ablated ASPN-induced signaling and migration. Clinically, ASPN was detected in the stroma of HER2/HER3-expressing human metastatic prostate cancer, supporting the clinical relevance of these findings and highlighting a potential therapeutic vulnerability. Antibody-drug conjugate (ADC) therapies designed to target HER2 (trastuzumab-deruxtecan) or HER3 (patritumab-deruxtecan) significantly diminished prostate cancer cell growth in vitro and tumor size in vivo, despite Aspn in the TME. Collectively, these findings indicate ASPN functions as a HER3 ligand to induce cellular migration, and inhibition with anti-HER2 or anti-HER3 ADC therapies highlights potential clinical utility for patients with metastatic castration-resistant prostate cancer that expresses HER2 or HER3.

Authors

Amanda B. Hesterberg, Hong Yuen Wong, Jorgen Jackson, Monika Antunovic, Brenda L. Rios, Evan Watkins, Riley E. Bergman, Brad A. Davidson, Sarah E. Ginther, Diana Graves, Elliott F. Nahmias, Jared A. Googel, Lillian B. Martin, Violeta Sanchez, Paula I. Gonzalez-Ericsson, Quanhu Sheng, Benjamin P. Brown, Jens Meiler, Kerry R. Schaffer, Jennifer B. Gordetsky, Ben H. Park, Paula J. Hurley

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Figure 10

ADCs designed to target HER2 or HER3 restrict growth of prostate cancer cells in vivo.

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ADCs designed to target HER2 or HER3 restrict growth of prostate cancer ...
(A) Schematic of PC3 subcutaneous xenografts grown to approximately 100 mm3 in NSG mice and then treated with vehicle (n = 6), 5 mg/kg P-DXd (n = 7), or 5 mg/kg T-DXd (n = 6) by retro-orbital injection weekly for 4 cycles. (B) Total weight of NSG mice with PC3 xenografts treated with vehicle, P-DXd, or T-DXd. (C) Growth curves of PC3 xenografts in NSG mice treated with vehicle, P-DXd, or T-DXd. (D) Tumor volume prior to P-DXd (pre-P-DXd) and T-DXd (pre-T-DXd) and after 4 cycles of weekly P-DXd (post-P-DXd) and T-DXd (post-T-DXd). (E and F) Photograph of representative NSG mice with PC3 xenografts (E) or isolated xenografts (F) treated with vehicle, P-DXd, or T-DXd at experimental endpoint. The fourth vehicle tumor was excluded from analyses due to the lack of a palpable tumor at treatment initiation. (G) Tumor weight of isolated PC3 xenografts in NSG mice treated with vehicle, P-DXd, or T-DXd at experimental endpoint. (H and I) Representative H&E, dual IHC/RNAscope for HER2 (IHC) and Aspn (RNAscope), and IHC for HER3 of PC3 xenografts treated with vehicle, P-DXd, or T-DXd. HER2, HER3, and Aspn expression (H) quantified by H-score (intensity × percent) (I). (J) Bubble plots of top 20 overlapping Hallmarks by GSEA of T-DXd– and P-DXd–treated xenografts compared with vehicle. Graphs shown as mean ± SEM and analyzed by multiple Student’s t test (C) or 1-way ANOVA with Tukey’s (D) or Dunnett’s post hoc analysis (G and I); *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001.