LAUSR

Modern immune and targeted therapies appear more effective against advanced melanoma in women than in men. Melanoma incidence is also lower in women. Similar sex differences are observed in other tumors that are not classically considered sex hormone responsive. Here, we show that much of the protective effect likely results from estrogen signaling through the G protein-coupled estrogen receptor (GPER) on tumor cells. Selective GPER activation in primary male and female melanocytes, and in melanoma cells, induced long-term changes that maintained a more differentiated cell state as defined by increased expression of well-established melanocyte differentiation antigens, increased pigment production, decreased proliferative capacity, and decreased expression of the oncodriver and stem cell marker c-Myc. GPER signaling also rendered melanoma cells more vulnerable to immunotherapy. Systemic delivery of a small-molecule, selective GPER agonist was well tolerated, and cooperated with PD-1 directed immune checkpoint blockade in melanoma-bearing mice to dramatically extend survival, with up to half of mice clearing their tumor. Complete responses were associated with immune memory that protected against rechallenge with naive tumor cells. Specific GPER activation in the BRaf-driven murine melanoma model (YUMM1.7) also delayed resistance to targeted BRaf inhibition in vivo. Similar antitumor responses were observed in genetically defined KRas-driven syngeneic pancreatic ductal carcinoma (PDAC) models. The GPER agonist used has favorable pharmacokinetics and oral bioavailability in mice and higher vertebrates and appears to have a large therapeutic window. Together, these data suggest that GPER may be a useful, pharmacologically accessible target for melanoma and other common cancers. This abstract is also being presented as Poster B15. Citation Format: Chris Natale, Jinyang Li, Jun Zhang, Cristina Aquirre, Ankit Dahal, Tzvete Dentchev, John Seykora, Ben Stanger, Todd Ridky. Specific activation of the G protein-coupled estrogen receptor inhibits melanoma and other cancers and potentiates immune and targeted therapies [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr PR16.