Mammalian target of rapamycin inhibitors are promising T cell lymphoma treatment agents that synergize with ERβ agonists in vitro but not in vivo (VAC3P.1061)

Abstract

Abstract mTOR signals through 2 complexes: mTORC1 and mTORC2. Approved cancer mTOR inhibitor drugs inhibit mTORC1 and are poorly effective against carcinomas and B cell lymphomas. There is thought that dual mTORC1/2 inhibitors could have better clinical efficacy. As mTOR regulates important T cell functions, we tested mTOR inhibitors in mouse EL4 T cell lymphoma. The mTORC1 inhibitor rapamycin potently suppressed EL4 proliferation in vitro, and significantly reduced EL4 tumor growth in vivo. AZD8055, a dual mTORC1/2 inhibitor, also inhibited EL4 cell proliferation in vitro, decreased in vivo tumor burden and improved survival in EL4 challenged mice, but no better than rapamycin. EL4 tumor growth was slower in females versus males, suggesting hormonal effects. As estrogen receptor (ER)β agonists reportedly can treat lymphomas we tested them. We found that ERβ agonists altered EL4 mTOR signals and a novel ERβ/mTOR physical interaction (mTORC2>>mTORC1) in EL4 by GST pull-down. The ERβ agonist S-equol synergized with AZD8055 to inhibit EL4 cell proliferation in vitro but did not alter EL4 tumor growth in vivo nor boost AZD8055-mediated EL4 growth suppression or survival in vivo. EL4 tumors from AZD8055 treated mice had reduced viability and proliferation (Ki67) without affecting CD3+ T cell Ki67. AZD8055 treated ID8 ovarian cancer in vivo but rapamycin did not, suggesting T cell lymphomas could respond to mTOR inhibitors better than carcinomas. ERβ effects also deserve more study.