Abstract 922: Preclinical anticancer activity of LSZ102, a novel oral selective estrogen receptor degrader targeting wild-type and mutant ER

Abstract

Estrogen receptor (ER) blockade is a well-established therapeutic approach in ER+ breast cancer. A novel oral selective estrogen receptor degrader (SERD), LSZ102, is in development. LSZ102 induces proteasome-mediated degradation of both wild type and mutant ERα in MCF-7 cells. LSZ102 also inhibits transcription of ERα target genes and results in a decrease in cell proliferation in a dose dependent manner. Expression of ERα Y537S results in a shift in inhibition of cell proliferation upon incubation with either LSZ102 or fulvestrant; however, the shift with LSZ102 was less severe. Similarly, LSZ102 induced a more pronounced level of ERα degradation than fulvestrant in the Y537S mutant MCF7 cells. Overall, LSZ102 is effective in the wild type and Y537S ERα mutant setting in vitro. In vivo, LSZ102 treatment of ER+ breast cancer xenografts resulted in inhibition of ERα regulated transcripts and a decrease in ERα protein levels. In the MCF7 xenograft model, expression of ERα Y537S resulted in reduced activity by fulvestrant, but not by LSZ102. In vivo, LSZ102 exhibited single agent and combination efficacy upon co-administration with the CDK4/6 inhibitor ribociclib and the alpha-specific PI3K inhibitor alpelisib. LSZ102 is currently in a Phase I clinical trial in patients with ER+ breast cancer in which it is tested as a single agent, and in combination with either ribociclib or alpelisib. Citation Format: L. Alex Gaither, Choi Lai Tiong Yip, Chunrong Wang, Weiyi Toy, Qing Sheng, Jinyun Chen, Yuji Mishina, Rita Das, Stefan Peukert, Alice Loo, Sarat Chandarlapaty, Adam Crystal, Tinya J. Abrams. Preclinical anticancer activity of LSZ102, a novel oral selective estrogen receptor degrader targeting wild-type and mutant ER [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 922.