Journal of Cancer Research and Treatment
ISSN (Print): 2374-1996 ISSN (Online): 2374-2003 Website: http://www.sciepub.com/journal/jcrt Editor-in-chief: Jean Rommelaere
Open Access
Journal Browser
Go
Journal of Cancer Research and Treatment. 2021, 9(2), 32-39
DOI: 10.12691/jcrt-9-2-2
Open AccessArticle

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

Chenchen Wang1, Li Han2, Ming Ding1, Xiaoxiao Wang1 and Yunhua Hou1,

1Hemato-Oncology, Minhang Hospital, Fudan University, Shanghai, China

2Department of Medical Examination Center, the Affiliated Zhongshan Hospital of Dalian University, Dalian, China

Pub. Date: November 10, 2021

Cite this paper:
Chenchen Wang, Li Han, Ming Ding, Xiaoxiao Wang and Yunhua Hou. LOR-253 Overcomes Resistance to ABT-199 by Targeting MTF1 in AML. Journal of Cancer Research and Treatment. 2021; 9(2):32-39. doi: 10.12691/jcrt-9-2-2

Abstract

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.

Keywords:
acute myeloid leukemia ABT-199 resistance MTF1 transcriptional reprogramming

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

References:

[1]  Sayad A, Hajifathali A, Hamidieh AA, Roshandel E, Taheri M: HOTAIR Long Noncoding RNA is not a Biomarker for Acute Myeloid Leukemia (AML) in Iranian Patients. Asian Pacific journal of cancer prevention: APJCP 2017, 18(6): 1581-1584.
 
[2]  Bruserud O, Aasebo E, Hernandez-Valladares M, Tsykunova G, Reikvam H: Therapeutic targeting of leukemic stem cells in acute myeloid leukemia - the biological background for possible strategies. Expert opinion on drug discovery 2017, 12(10): 1053-1065.
 
[3]  Grove CS, Vassiliou GS: Acute myeloid leukaemia: a paradigm for the clonal evolution of cancer? Disease models & mechanisms 2014, 7(8): 941-951.
 
[4]  Shallis RM, Wang R, Davidoff A, Ma X, Zeidan AM: Epidemiology of acute myeloid leukemia: Recent progress and enduring challenges. Blood reviews 2019, 36: 70-87.
 
[5]  Farge T, Saland E, de Toni F, Aroua N, Hosseini M, Perry R, Bosc C, Sugita M, Stuani L, Fraisse M et al: Chemotherapy-Resistant Human Acute Myeloid Leukemia Cells Are Not Enriched for Leukemic Stem Cells but Require Oxidative Metabolism. Cancer discovery 2017, 7(7): 716-735.
 
[6]  Cornelison R, Llaneza DC, Landen CN: Emerging Therapeutics to Overcome Chemoresistance in Epithelial Ovarian Cancer: A Mini-Review. International journal of molecular sciences 2017, 18(10).
 
[7]  Ruefli-Brasse A, Reed JC: Therapeutics targeting Bcl-2 in hematological malignancies. The Biochemical journal 2017, 474(21): 3643-3657.
 
[8]  Anderson MA, Deng J, Seymour JF, Tam C, Kim SY, Fein J, Yu L, Brown JR, Westerman D, Si EG et al: The BCL2 selective inhibitor venetoclax induces rapid onset apoptosis of CLL cells in patients via a TP53-independent mechanism. Blood 2016, 127(25): 3215-3224.
 
[9]  Leverson JD, Sampath D, Souers AJ, Rosenberg SH, Fairbrother WJ, Amiot M, Konopleva M, Letai A: Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax. Cancer discovery 2017, 7(12): 1376-1393.
 
[10]  Choudhary GS, Al-Harbi S, Mazumder S, Hill BT, Smith MR, Bodo J, Hsi ED, Almasan A: MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies. Cell death & disease 2015, 6: e1593.
 
[11]  Esteve-Arenys A, Valero JG, Chamorro-Jorganes A, Gonzalez D, Rodriguez V, Dlouhy I, Salaverria I, Campo E, Colomer D, Martinez A et al: The BET bromodomain inhibitor CPI203 overcomes resistance to ABT-199 (venetoclax) by downregulation of BFL-1/A1 in in vitro and in vivo models of MYC+/BCL2+ double hit lymphoma. Oncogene 2018, 37(14): 1830-1844.
 
[12]  Zhao X, Ren Y, Lawlor M, Shah BD, Park PMC, Lwin T, Wang X, Liu K, Wang M, Gao J et al: BCL2 Amplicon Loss and Transcriptional Remodeling Drives ABT-199 Resistance in B Cell Lymphoma Models. Cancer cell 2019, 35(5): 752-766 e759.
 
[13]  Shi Y, Amin K, Sato BG, Samuelsson SJ, Sambucetti L, Haroon ZA, Laderoute K, Murphy BJ: The metal-responsive transcription factor-1 protein is elevated in human tumors. Cancer biology & therapy 2010, 9(6): 469-476.
 
[14]  Devergnas S, Chimienti F, Naud N, Pennequin A, Coquerel Y, Chantegrel J, Favier A, Seve M: Differential regulation of zinc efflux transporters ZnT-1, ZnT-5 and ZnT-7 gene expression by zinc levels: a real-time RT-PCR study. Biochemical pharmacology 2004, 68(4): 699-709.
 
[15]  Rusan M, Li K, Li Y, Christensen CL, Abraham BJ, Kwiatkowski N, Buczkowski KA, Bockorny B, Chen T, Li S et al: Suppression of Adaptive Responses to Targeted Cancer Therapy by Transcriptional Repression. Cancer discovery 2018, 8(1): 59-73.
 
[16]  Gonda TJ, Ramsay RG: Directly targeting transcriptional dysregulation in cancer. Nature reviews Cancer 2015, 15(11): 686-694.
 
[17]  Wang Y, Wang Y, Fan X, Song J, Wu H, Han J, Lu L, Weng X, Nie G: ABT-199-mediated inhibition of Bcl-2 as a potential therapeutic strategy for nasopharyngeal carcinoma. Biochemical and biophysical research communications 2018, 503(3): 1214-1220.
 
[18]  Luedtke DA, Niu X, Pan Y, Zhao J, Liu S, Edwards H, Chen K, Lin H, Taub JW, Ge Y: Inhibition of Mcl-1 enhances cell death induced by the Bcl-2-selective inhibitor ABT-199 in acute myeloid leukemia cells. Signal transduction and targeted therapy 2017, 2: 17012.
 
[19]  Luedtke DA, Su Y, Liu S, Edwards H, Wang Y, Lin H, Taub JW, Ge Y: Inhibition of XPO1 enhances cell death induced by ABT-199 in acute myeloid leukaemia via Mcl-1. Journal of cellular and molecular medicine 2018, 22(12): 6099-6111.
 
[20]  Local A, Zhang H, Benbatoul KD, Folger P, Sheng X, Tsai CY, Howell SB, Rice WG: APTO-253 Stabilizes G-quadruplex DNA, Inhibits MYC Expression, and Induces DNA Damage in Acute Myeloid Leukemia Cells. Molecular cancer therapeutics 2018, 17(6): 1177-1186.
 
[21]  Tsai CY, Sun S, Zhang H, Local A, Su Y, Gross LA, Rice WG, Howell SB: APTO-253 Is a New Addition to the Repertoire of Drugs that Can Exploit DNA BRCA1/2 Deficiency. Molecular cancer therapeutics 2018, 17(6): 1167-1176.