Targeting Semaphorin 7a signaling in preclinical models of endocrine therapy-resistant breast cancer.

Estrogen receptor-positive (ER+) breast cancers comprise more than 70% of breast cancers and are the leading cause of breast cancer-related deaths in women worldwide. Despite available therapies that target ER, recurrence occurs in many patients because of therapeutic resistance. Semaphorin 7a (SEMA7A) is emerging as a biomarker associated with poor prognosis and endocrine therapy resistance in patients with breast cancer. Survival analyses of patients with ER+ breast cancer treated with endocrine therapy suggest early recurrence in patients with SEMA7A+ tumors. Thus, establishing novel treatment strategies could improve outcomes for patients with ER+ SEMA7A+ breast cancer. In this article, we investigate mechanisms by which SEMA7A promotes resistance to endocrine therapy and its potential as a therapeutic target for ER+ breast cancer. Our results suggest that SEMA7A forms a protein complex with integrins β1 and β4, which results in AKT-mediated prosurvival signaling via its RGD domain. Using mouse models of ER+ breast cancer (FVB/N mice and TC11 tumor model), we show reduced growth of SEMA7A+ tumors with PI3K inhibitors (GCT-007:10 mg/kg daily and alpelisib: 20 mg/kg daily), alone or in combination with tamoxifen (0.5 mg/100 µL, every third day). The combination of an anti-SEMA7A antibody (SmAbH1; 100-250 µg/100 µL, every other day) and fulvestrant (83 mg/kg, every 5 days) also revealed that direct inhibition of SEMA7A via SmAbH1 significantly reduces tumor growth of SEMA7A-expressing tumors and that the efficacy of SmAbH1 is not diminished by the standard-of-care fulvestrant. Overall, our studies suggest that patients with ER+ SEMA7A+ tumors should be candidates for PI3K-targeted therapies or anti-SEMA7A-based therapy.