Abstract 1786: SM-88, D/L-alpha-metyrosine, is a novel anti-cancer agent in estrogen receptor positive breast cancer

Abstract

Abstract Breast cancer is the second most common cause of death from cancer in women in the United States after lung cancer. Estrogen receptor positive (ER+) breast cancer comprises 70% of all breast cancer cases. Antiestrogens and CDK4/6 inhibitors are now part of standard of care therapies for advanced and metastatic ER+ breast tumors. Unfortunately, resistance to these therapies is prevalent and metastatic breast cancer remains an incurable disease. Since drug resistant cancer cells often have deregulated metabolic pathways, we tested the efficacy of a novel dysfunctional tyrosine, SM-88 (D,L-alpha-metyrosine; racemetyrosine), alone or in combination with sub-toxic doses of conditioning agents, methoxsalen, phenytoin, and sirolimus (MPS) in resistant cell models of ER+ breast cancer. In normal cells, tyrosine, a non-essential amino acid, is made from phenylalanine and not readily taken up by cells. Therefore, it is hypothesized that SM-88 uptake will be increased in cancer cells compared to normal cells. To evaluate whether SM-88 is a potential anti-cancer agent for drug resistant ER+ tumors, we used antiestrogens and CDK4/6 inhibitors sensitive (parental MCF7 and T47D cell lines) or resistant (MCF7-R and T47D-R) cells in this study. We show that cell proliferation was inhibited in both sensitive and resistant ER+ breast cancer cells at 72 h, however, the IC50 of SM-88 as a monotherapy was higher in resistant cells compared with sensitive cells, 5mM versus 2 mM, respectively. Combination of SM-88 and MPS had an additive effect and lowered the IC50 in both resistant and sensitive cells, 2mM versus 1mM, respectively. Both LAT1 and CD98, known transporters of tyrosine, were expressed in sensitive and resistant cells. Furthermore, SM-88 as a single agent or in combination with MPS resulted in the induction of incomplete autophagy in both sensitive and resistant cells. Apoptosis and DNA damage was noted in p53-wildtype MCF7 and MCF7-R but not in p53-mutant T47D and T47D-R cells with SM-88 monotherapy or in combination with MPS. Ongoing work is focused on further defining the biochemical pathways in drug sensitive and resistant cells that will further support the current clinical use of SM-88 in advanced ER+ breast cancer (ClinicalTrials.gov Identifier: NCT04720664). Collectively, we show that SM-88 is potentially a novel anti-cancer agent in drug resistant ER+ breast cancer. Citation Format: Diane M. Demas, Julie Collins, Ayesha N. Shajahan-Haq. SM-88, D/L-alpha-metyrosine, is a novel anti-cancer agent in estrogen receptor positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1786.