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

Estrogen receptor-positive (ER+) breast cancers (BC) comprise over 70% of breast cancers and are the leading cause of BC-related deaths in women worldwide. Despite available therapies that target ER, recurrence occurs in many patients due to therapeutic resistance. Semaphorin 7a (SEMA7A) is emerging as a biomarker associated with poor prognosis and endocrine therapy resistance in BC patients. Survival analyses of ER+ BC patients 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+ BC. In this paper, we investigate mechanisms by which SEMA7A promotes resistance to endocrine therapy and its potential as a therapeutic target for ER+ BC. Our results suggest that SEMA7A forms a protein complex with integrins B1 and B4, which results in AKT-mediated pro-survival signaling via its RGD domain. Using mouse models of ER+BC (FVB/N mice, TC11 tumor model), we show reduced growth of SEMA7A+ tumors with PI3K inhibitors (GCT-007:10 mg/kg daily, alpelisib: 20mg/kg daily), alone or in combination with tamoxifen (0.5mg/100uL, every 3rd day). Combination of an anti-SEMA7A antibody (SmAbH1) (100-250 ug/100uL, 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.