Type: Oral
Session: 604. Molecular Pharmacology and Drug Resistance: Myeloid Neoplasms: Personalized and Combinatorial Approaches to Target Vulnerabilities in Myeloid Malignancies
Hematology Disease Topics & Pathways:
apoptosis, Research, Acute Myeloid Malignancies, AML, Translational Research, bioinformatics, Diseases, Biological Processes, Myeloid Malignancies, Technology and Procedures, Minimal Residual Disease , molecular testing
Using unbiased whole transcriptomic analysis of naïve and resistant PDXs (n=78 samples), we found common pathways of resistance where positive enrichment was observed for cytokine-cytokine receptor interactions, xenobiotics biodegradation, metabolic pathways, Hippo signaling, and Ras signaling in resistant compared to treatment-naïve PDXs. Conversely, mechanisms relating to DNA repair and replication, such as base excision repair, mismatch repair, and homologous recombination, were negatively enriched. Moreover, pathways associated with specific drug resistance were also observed. One of the known multi-drug resistance mechanisms to chemotherapy drugs in AML is increased expression of efflux pumps from the superfamily of ATP binding cassette. We found enrichment in ABC transporter family pathway signatures in all 3 PDX models, DFAM-61786, DFAM-15354, and DFAM-61345, resistant to quizartinib, birinapant, and JQ-1 and validated higher drug-efflux activity in quizartinib and birinapant resistant model using calcein-AM efflux assay.
We finally tested whether DBP could predict in vivo response of patient myeloblasts in PDX models. We tested in vivo sensitivity to 5 drugs of disparate mechanisms of action: birinapant and LCL-161 (SMAC mimetics), JQ-1 (BRD-4 inhibitor), venetoclax (BCL-2 antagonist), and quizartinib (FLT-3 inhibitor) in 4-9 different PDX models each. Using ex vivo DBP assay, we identified drugs that prime not only treatment naïve PDXs but also R/R PDXs. We identified persistent in vivo activity in a drug-specific manner, with BH3 mimetics and HDAC inhibitors showing overlapping activity across different drug-resistant models. Overall, we demonstrate that acquired resistance to targeted therapy in AML is accompanied by common mechanism of reduction in mitochondrial priming along with drug-specific resistance mechanisms. Further, we find that, even in the context of a multiply-resistant PDX model, DBP can still identify therapeutic vulnerabilities that can be efficaciously exploited in vivo.
Disclosures: Luskin: Novartis: Honoraria; Pfizer: Honoraria; Novartis: Research Funding; Jazz: Honoraria; AbbVie: Research Funding. Kallioniemi: Pelago: Other: Joint Grant; Takara: Other: Joint Grant; AstraZeneca: Other: Joint Grant; Sartar Therapeutics: Other: Co-founder and stockholder; MediSapiens: Other: Co-founder and stockholder; Vysis-Abbot: Patents & Royalties. Garcia: New Wave: Research Funding; Prelude: Research Funding; Servier: Consultancy; Pfizer: Research Funding; Gilead: Consultancy; Genentech: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; AbbVie: Consultancy, Research Funding; Astellas: Consultancy; AstraZeneca: Research Funding.
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