THU546 A Lasofoxifene/Elacestrant Hybrid Antiestrogen Shows Effective Anti-tumoral Activities In Y537S ESR1 Breast Cancer Xenografts

Disclosure: K.S. Young: None. G.R. Hancock: None. S. Kregel: None. S.W. Fanning: Advisory Board Member; Self; Olema Oncology. Grant Recipient; Self; Olema Oncology. In the United States, breast cancer is the second leading cause of cancer related deaths among women. Over 70 percent of these breast cancer cases are classified as overexpressing Estrogen Receptor alpha (ERα), denoting that the hormone estrogen fuels the cancer growth. In ER+ breast cancer patients, a distinct tyrosine to serine missense mutation at position 537 (Y537S) leads to hormone- independent ERα activity, causing drug resistance and increased metastatic potential. By favoring the active conformation of ERα, the Y537S mutation reduces binding affinity of small molecule drugs by 5-10 fold. Additionally, this mutation adversely effects the allosteric rearrangement of the receptor that is needed to achieve therapeutic efficacy. Recently, we identified a common structural interaction that distinguishes effective versus ineffective therapeutic antagonists in Y537S breast cancer cells. Based on this relationship, we have developed a new isoquinoline- based antiestrogen (T6I-29-1A) to aid in interpretation of the relationship between ligand binding pose and antagonistic efficacy. Our data suggest that this novel pose effectively antagonizes mutant ERα in breast cancer cells by significantly blunting cell proliferation and downregulating transcriptional activity. Importantly, T6I-29-1A shows potent anti-tumoral activity in ectopic murine xenografts of Y537S ESR1 MCF7 cells, is orally available, and shows a favorable DMPK and ADME profile. Additionally, mice treated with T6I-29-1A exhibited decreased distant metastases compared to hormone-only control. Collectively, these studies point to a distinct relationship between ERα ligand binding pose and novel anti-metastatic activities in drug resistant Y537S ESR1 breast cancer cells. Presentation: Thursday, June 15, 2023