Abstract B025: ASCL1 and SOX2 expression levels predict sensitivity to LSD1 inhibition with iadademstat in small cell lung cancer

Abstract

Abstract Lysine Specific Demethylase 1 (LSD1, also known as KDM1A) is a member of the FAD-containing family of lysine demethylases and is generally involved in repressing transcription by specifically removing methyl groups from mono- and di-methylated lysine 4 of histone 3 - epigenetic marks commonly associated with actively transcribed genes. LSD1 over-expression has been associated with disease progression and worse prognosis in several human cancers, and its inhibition has been shown to reduce cancer cell growth, migration and invasion. LSD1 has therefore been recognized as a target of interest for the development of new drugs to treat cancer. Iadademstat (aka ORY-1001), a highly potent and selective LSD1 inhibitor (LSD1i) in clinical development for malignant indications, and other LSD1is, have been reported to be effective for the treatment of small cell lung cancer (SCLC) in in vitro and in vivo models. However, the published data indicate that while certain SCLC are highly sensitive to LSD1 inhibition this sensitivity is not a universal feature of SCLC cells raising the need to develop methods for identifying sensitive SCLC tumors. Herein, we report the identification of the predictive biomarkers ASCL1 and SOX2 for the enrichment of the SCLC population more likely to respond to iadademstat and other LSD1is. Response to LSD1is was evaluated in a broad panel of SCLC cell lines (from viability assay data obtained internally at Oryzon Genomics with iadademstat and from data published elsewhere using other LSD1is). Additionally, analysis of gene expression was performed in this cell line panel using internal and publicly available datasets (Affymetrix, CCLE). This analysis revealed that the transcription factors ASCL1 and SOX2 are more likely to be highly expressed in SCLC cell lines that respond to LSD1 inhibition. Moreover, the mRNA levels of these biomarkers were highly correlated with their protein levels in both SCLC cell lines and in patient-derived xenografts. In particular, immunofluorescence staining of these patient-derived SCLC samples can discriminate different degrees of ASCL1 and SOX2 protein expression levels (none, low, medium, high), which correlate with their mRNA levels determined by RNAseq in the same samples. Moreover, analysis of ASCL1 and SOX2 protein levels analyzed internally by immunofluorescence in 40 SCLC biopsies showed that 58% samples concomitantly expressed medium to high levels of both biomarkers. Taken together, these data suggest that medium to high expression of both ASCL1 and SOX2 define a SCLC population more likely to respond to LSD1 inhibition, and that this population could account for nearly 60% of SCLC cases. Therefore, ASCL1 and SOX2 expression could be used as predictive biomarkers for personalized medicine with iadademstat in SCLC patients and clinical research to validate this hypothesis is warranted. Citation Format: Natalia Sacilotto, Serena Lunardi, Filippo Ciceri, Cristina Mascaro, Tamara Maes, Ana Limon, Douglas V. Faller. ASCL1 and SOX2 expression levels predict sensitivity to LSD1 inhibition with iadademstat in small cell lung cancer. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B025.