Acquired Resistance to ABT-737 in Lymphoma Cells That Up-regulate MCL-1 and BFL-1

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2010 Mar 4

PMID 20197552

Citations 211

Authors

Derek Yecies

Nicole E Carlson

Jing Deng

Anthony Letai

Affiliations

Soon will be listed here.

Abstract

ABT-737 is a small-molecule antagonist of BCL-2 currently under evaluation in clinical trials in the oral form of ABT-263. We anticipate that acquired resistance to this promising drug will inevitably arise. To study potential mechanisms of resistance to ABT-737, we derived resistant lines from initially sensitive OCI-Ly1 and SU-DHL-4 lymphoma cell lines via long-term exposure. Resistance was based in the mitochondria and not due to an inability of the drug to bind BCL-2. Resistant cells had increased levels of BFL-1 and/or MCL-1 proteins, which are not targeted by ABT-737. Proapoptotic BIM was displaced from BCL-2 by ABT-737 in both parental and resistant cells, but in resistant cells, BIM was sequestered by the additional BFL-1 and/or MCL-1. Decreasing MCL-1 levels with flavopiridol, PHA 767491, or shRNA restored sensitivity to ABT-737 resistant cells. MCL-1 was up-regulated not by protein stabilization but rather by increased transcript levels. Surprisingly, in addition to stable increases in MCL-1 transcript and protein in resistant cells, there was a dynamic increase within hours after ABT-737 treatment. BFL-1 protein and transcript levels in resistant cells were similarly dynamically up-regulated. This dynamic increase suggests a novel mechanism whereby modulation of antiapoptotic protein function communicates with nuclear transcriptional machinery.

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References

Tahir S, Yang X, Anderson M, Morgan-Lappe S, Sarthy A, Chen J . Influence of Bcl-2 family members on the cellular response of small-cell lung cancer cell lines to ABT-737. Cancer Res. 2007; 67(3):1176-83. DOI: 10.1158/0008-5472.CAN-06-2203. View

Safa A, Glover C, Sewell J, MEYERS M, Biedler J, Felsted R . Identification of the multidrug resistance-related membrane glycoprotein as an acceptor for calcium channel blockers. J Biol Chem. 1987; 262(16):7884-8. View

van Delft M, Wei A, Mason K, Vandenberg C, Chen L, Czabotar P . The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell. 2006; 10(5):389-99. PMC: 2953559. DOI: 10.1016/j.ccr.2006.08.027. View

Willis S, Chen L, Dewson G, Wei A, Naik E, Fletcher J . Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev. 2005; 19(11):1294-305. PMC: 1142553. DOI: 10.1101/gad.1304105. View

Gaizo Moore V, Brown J, Certo M, Love T, Novina C, Letai A . Chronic lymphocytic leukemia requires BCL2 to sequester prodeath BIM, explaining sensitivity to BCL2 antagonist ABT-737. J Clin Invest. 2007; 117(1):112-21. PMC: 1716201. DOI: 10.1172/JCI28281. View

Letai A . Diagnosing and exploiting cancer's addiction to blocks in apoptosis. Nat Rev Cancer. 2008; 8(2):121-32. DOI: 10.1038/nrc2297. View

Hsu Y, Youle R . Nonionic detergents induce dimerization among members of the Bcl-2 family. J Biol Chem. 1997; 272(21):13829-34. DOI: 10.1074/jbc.272.21.13829. View

Byrd J, Lin T, Dalton J, Wu D, Phelps M, Fischer B . Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia. Blood. 2006; 109(2):399-404. PMC: 1785084. DOI: 10.1182/blood-2006-05-020735. View

Cleary M, Sklar J . Nucleotide sequence of a t(14;18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint-cluster region near a transcriptionally active locus on chromosome 18. Proc Natl Acad Sci U S A. 1985; 82(21):7439-43. PMC: 391360. DOI: 10.1073/pnas.82.21.7439. View

10.

Lin X, Morgan-Lappe S, Huang X, Li L, Zakula D, Vernetti L . 'Seed' analysis of off-target siRNAs reveals an essential role of Mcl-1 in resistance to the small-molecule Bcl-2/Bcl-XL inhibitor ABT-737. Oncogene. 2006; 26(27):3972-9. DOI: 10.1038/sj.onc.1210166. View

11.

Cheng E, Wei M, Weiler S, Flavell R, Mak T, LINDSTEN T . BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell. 2001; 8(3):705-11. DOI: 10.1016/s1097-2765(01)00320-3. View

12.

Chipuk J, Fisher J, Dillon C, Kriwacki R, Kuwana T, Green D . Mechanism of apoptosis induction by inhibition of the anti-apoptotic BCL-2 proteins. Proc Natl Acad Sci U S A. 2008; 105(51):20327-32. PMC: 2629294. DOI: 10.1073/pnas.0808036105. View

13.

Oltersdorf T, Elmore S, Shoemaker A, Armstrong R, Augeri D, Belli B . An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005; 435(7042):677-81. DOI: 10.1038/nature03579. View

14.

Chen S, Dai Y, Harada H, Dent P, Grant S . Mcl-1 down-regulation potentiates ABT-737 lethality by cooperatively inducing Bak activation and Bax translocation. Cancer Res. 2007; 67(2):782-91. DOI: 10.1158/0008-5472.CAN-06-3964. View

15.

Brunelle J, Ryan J, Yecies D, Opferman J, Letai A . MCL-1-dependent leukemia cells are more sensitive to chemotherapy than BCL-2-dependent counterparts. J Cell Biol. 2009; 187(3):429-42. PMC: 2779245. DOI: 10.1083/jcb.200904049. View

16.

Letai A, Bassik M, Walensky L, Sorcinelli M, Weiler S, Korsmeyer S . Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell. 2002; 2(3):183-92. DOI: 10.1016/s1535-6108(02)00127-7. View

17.

Montagnoli A, Valsasina B, Croci V, Menichincheri M, Rainoldi S, Marchesi V . A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity. Nat Chem Biol. 2008; 4(6):357-65. DOI: 10.1038/nchembio.90. View

18.

Maurer U, Charvet C, Wagman A, Dejardin E, Green D . Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell. 2006; 21(6):749-60. DOI: 10.1016/j.molcel.2006.02.009. View

19.

McDonnell T, Deane N, Platt F, Nunez G, Jaeger U, McKearn J . bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell. 1989; 57(1):79-88. DOI: 10.1016/0092-8674(89)90174-8. View

20.

Gojo I, Zhang B, Fenton R . The cyclin-dependent kinase inhibitor flavopiridol induces apoptosis in multiple myeloma cells through transcriptional repression and down-regulation of Mcl-1. Clin Cancer Res. 2002; 8(11):3527-38. View