LOR-253 Overcomes Resistance to ABT-199 by Targeting MTF1 in AML

Introduction: Chemoresistance is one of the major challenges for the acute myeloid leukemia (AML) treatment. Venetoclax (ABT-199), a selective small molecule BCL-2 inhibitor, is being clinically vetted and is an effective therapy for some B-cell lymphomas, yet many patients who initially respond to ABT-199 develop resistance. Thus, enhancing the sensitivity of resistant cells to chemotherapy is a great interest to clinical trial. Method: The resistant cell lines were generated by culturing in the medium containing ABT-199. CCK8 analysis was used to detect the cell viability. Flowcytometric analysis with Annexin-V/PI was used to test the apoptosis. CRISPR/Cas9 by lentivirus delivering well-validated shRNAs in pLKO.1 vector was used to knockout the expression of MTF1. Western blot with the antibodies was used to determine the expression of the molecules. Clonogenic growth assay was used to determine the growth of parental and DTEP cells. Results: Here we report that resistance to the BCL-2 targeting drug ABT-199 in AML cell lines evolves from outgrowth of persister clones harbor BCL2. Furthermore, persister status is generated via adaptive super-enhancer remodeling that reprograms transcription and offers opportunities for overcoming ABT-199 resistance. Notably, pharmacogenomic screens revealed that persisters are vulnerable to inhibition of metal regulatory transcription factor 1 (MTF1), which is essential for the transcriptional reprogramming that drives and sustains ABT-199 resistance. Conclusion: LOR-253, which is a MTF1-targeting agent, add novel insights to overcome ABT-199-resistance in B-cell lymphomas.