Abstract 2262: Genomic profiling of leukemic cell lines, responders vs. non-responders to Narazaciclib (HX301 or ON123300), a novel kinase inhibitor with activity against CSF1R and FLT3

Abstract

Abstract Acute myeloid leukemia (AML) is an aggressive myeloid leukemia with global annual mortality ~150,000. While standard of care (SOC) of the 1st -line treatment being mainly induction chemotherapy, available targeted therapies cover rather limited patients carrying specific driver mutations (IDH mutations and FLT3-ITR). We previously reported a novel kinase inhibitor, Narazaciclib with strong anti-CSF1R activity (IC50 0.7nM) as well as anti-FLT3 (IC50 7nM), and also thus anti-AML activity for certain AML experimental models, as shown in vitro and in vivo (AACR Annual Meeeting, 2023). In the present study, we assessed the impact of HX301 on the in vitro proliferations of a panel of leukemic cell lines (n = 54), including a panel of AML cell lines (n = 33), that have been parallelly genomic-profiled by whole-exome sequencing and whole-transcriptome sequencing. We then set out to analyze the proliferation data and the genomic data, in attempt to elucidate genes and pathways that may be associated with the treatment responses. The biomarker analysis has been performed on gene expression, mutation and copy number variation levels, and the data been presented using common methodologies, including principal component analysis, differential expression analysis, correlation analysis, Gene Ontology enrichment analysis, gene set variation analysis, somatic gene mutation analysis, and copy number variation analysis, etc. Some of the observations have been made: 1) differential expression analysis on all leukemic cell lines shows that 254 genes have been positively associated with the responders; while expression of 191 genes are negatively correlated with AUC, i.e. positively associated with response, as revealed by Spearman correlation analysis; 2) Gene Ontology enrichment analysis revealed these response related genes are mostly involved in myeloid leukocyte activation and defense response; 3) all FLT3-ITD AML lines are responders, presumably due to the FLT3i activity of HX301; 4) CSF1R expression levels seem not correlated to drug responses; 5) pathway analysis on non FLT3-ITD AML lines reveals that STAT5 activation downstream of FLT3 signaling, IL7 pathway and NFKB pathway are significantly associated with better response. Finally, we are also attempted to use statistics learning to reveal genes, as a potential predictive biomarker, that may be correlated to drug response. Citation Format: Jia Xue, Tao Yang, Hang Ke, Sheng Guos, Henry Qixiang Li. Genomic profiling of leukemic cell lines, responders vs. non-responders to Narazaciclib (HX301 or ON123300), a novel kinase inhibitor with activity against CSF1R and FLT3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2262.