Abstract 6290: Characterizing antitumor responses to EXS-74539, a novel, reversible LSD1 inhibitor with potential in small-cell lung cancer

Abstract

Abstract Background: Lysine demethylase 1 (LSD1) is a potentially important target in oncology due to its role in demethylating histones and suppressing expression of genes required for cellular differentiation. In small-cell lung cancer (SCLC), high LSD1 expression is associated with suppressed differentiation pathways. Although selective LSD1 compounds are in clinical development, understanding of the molecular markers of tumor sensitivity to inhibition of LSD1 inhibition is incomplete. Methods: We report on the pharmacological characterization of EXS-74539, a potent, selective and reversible LSD1 inhibitor. We assessed EXS-74539 efficacy in in vitro and in vivo SCLC cell line models, encompassing the four molecular subtypes of SCLC tumor cells previously proposed (Rudin et al, 2019), based on differential expression of key transcription regulators, ASCL1, NEUROD1, POU2F3 and YAP1. Results: In vitro, EXS-74539 demonstrated similar anti-proliferative activity against both neuroendocrine (NCI-H1417 and NCI-H69, ASCL1 sub-type) and non-neuroendocrine (NCI-H526: POU2F3) SCLC cell lines, with IC50 values of 28, 12 and 11 nM, respectively. In vitro exposure of these cell lines to EXS-74539 led to concentration-dependent alterations in differentiation-associated genes. However, in vivo, significant differences in antitumor growth response upon LSD1 inhibition were observed between the cell lines; NCI-H69 tumor growth was unaffected following treatment with EXS-74539 and an irreversible LSD1 inhibitor at dose regimens which were efficacious in the NCI-H1417 and NCI-H5126 models. We describe in vitro and in vivo gene expression correlations associated with LSD1 sensitivity. Conclusions: The reversible LSD1 inhibitor, EXS-74539, is a potent inhibitor of SCLC cell line proliferation and shows in vivo efficacy. Characterizing SCLC cell line sensitivity in vitro and in vivo identified gene signatures that may have use as markers of sensitivity, which we are currently characterizing and validating in human SCLC patient samples. Rudin et al., Nat Rev Cancer, 2019 Citation Format: Andrew Payne, Manisha Naik, Simon Richards, Victor Sebastian Perez, Maria Dominguez. Characterizing antitumor responses to EXS-74539, a novel, reversible LSD1 inhibitor with potential in small-cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6290.