Identification of Asporin as a HER3 ligand that exposes a therapeutic vulnerability in metastatic prostate cancer

Cancer-associated fibroblasts (CAF) are part of the tumor microenvironment that enable cancer cells to establish metastases, but the mechanisms of these interactions are not fully known. Herein, we identify a novel paracrine mechanism in which CAF-secreted asporin (ASPN) activates ErbB signaling and subsequent migration of adjacent metastatic prostate cancer cells. Our data support that ASPN binds directly to HER3 to induce HER2/HER3 heterodimerization and activation of the PI3-kinase and MAP-kinase pathways. Genetic and therapeutic inhibition of HER2/HER3 ablated ASPN-induced signaling and migration. Small molecule and antibody-drug conjugates targeting HER2/HER3 demonstrated efficacy in vitro, with near complete resolution of tumors in vivo. Clinically, over 50% of human prostate cancer metastases show expression of HER2/HER3, along with ASPN expressing CAF. Collectively, these findings support ASPN functions as a HER3 ligand to induce cellular migration which can be targeted with anti-HER2/HER3 therapies, highlighting the potential clinical benefit for patients with metastatic prostate cancer. 1 million proliferative human PC3 cells in a 1:1 mixture of ice-cold PBS and Matrigel were subcutaneously injected into the flanks of 11-week-old NSG male mice (100 μL/mouse). Mice were monitored and tumor measurements obtained three times a week using electronic calipers once tumors were palpable. Tumor volume was calculated by [(length)2 x width]/2. When tumors were 90 mm3, mice were randomized and treated with 5 mg/kg T-DXd or P-DXd, or Vehicle Control (PBS) once a week via retro-orbital injection for 5 cycles. Tumors were harvested for analysis at experimental endpoint.