Abstract Acute myeloid leukemia or AML encompasses diverse molecular subtypes driven by distinct transcriptional and genetic programs that influence therapeutic response. AOH1996 which is a PCNA-dependent replication stress pathway inhibitor has demonstrated preclinical activity in AML. However biomarkers that may predict sensitivity across heterogeneous AML subgroups remain undefined. We first applied integrative multiomic analysis to begin defining the molecular contexts in which AOH1996 may be most effective. Transcriptomic, genomic, and proteomic datasets from PRISM, DepMap, and other curated subtype annotations were integrated with AOH1996 response metrics also known as AUC. Initial analyses focused on quantitative assessment of MYC RNA expression relative to AOH1996 sensitivity using a quadrant based visualization framework, and ongoing multi-omic analyses incorporating mutational backgrounds. Pathway activity scores, and protein level features are being used to explore broader biomarker patterns across AML models. Guided by these computational findings we are developing complementary in vitro studies in a panel of molecularly annotated AML models to functionally probe AOH1996 response, with planned readouts broadly focused on cell growth, cell cycle behavior, and stress associated phenotypes consistent with replication stress and innate immune pathway engagement. Preliminary computational results reveal subtype dependent variation in the relationship between MYC expression and AOH1996 response which aligns with MYC’s established role in driving transcriptional load and replication stress and nominating MYC expression as a biologically plausible candidate biomarker. Together, this integrated multiomics and emerging experimental framework supports the feasibility of biomarker-guided evaluation of AOH1996 across AML subtypes and provides a foundation for future translational studies aimed at molecularly informed therapeutic stratification. Citation Format: Hamsini Kala, Dana Abou Abbas, Robert J. Hickey, Linda H. Malkas, Caroline M. Li, Robert G. Lingeman, Guido Marcucci, Le Xuan Truong Nguyen, Brian Ball, Amanda Blackmon, Melissa Ronan, Jennifer Roth, Matthew G. Rees. Integrative multiomics and functional studies to identify biomarkers of AOH1996 sensitivity across AML subtypes abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3749.
Kala et al. (Fri,) studied this question.