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Targeting MCL-1/BCL-XL Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia.

Publication ,  Journal Article
Lin, KH; Winter, PS; Xie, A; Roth, C; Martz, CA; Stein, EM; Anderson, GR; Tingley, JP; Wood, KC
Published in: Sci Rep
June 10, 2016

ABT-199, a potent and selective small-molecule antagonist of BCL-2, is being clinically vetted as pharmacotherapy for the treatment of acute myeloid leukemia (AML). However, given that prolonged monotherapy tends to beget resistance, we sought to investigate the means by which resistance to ABT-199 might arise in AML and the extent to which those mechanisms might be preempted. Here we used a pathway-activating genetic screen to nominate MCL-1 and BCL-XL as potential nodes of resistance. We then characterized a panel of ABT-199-resistant myeloid leukemia cell lines derived through chronic exposure to ABT-199 and found that acquired drug resistance is indeed driven by the upregulation of MCL-1 and BCL-XL. By targeting MCL-1 and BCL-XL, resistant AML cell lines could be resensitized to ABT-199. Further, preemptively targeting MCL-1 and/or BCL-XL alongside administration of ABT-199 was capable of delaying or forestalling the acquisition of drug resistance. Collectively, these data suggest that in AML, (1) the selection of initial therapy dynamically templates the landscape of acquired resistance via modulation of MCL-1/BCL-XL and (2) appropriate selection of initial therapy may delay or altogether forestall the acquisition of resistance to ABT-199.

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Published In

Sci Rep

DOI

EISSN

2045-2322

Publication Date

June 10, 2016

Volume

6

Start / End Page

27696

Location

England

Related Subject Headings

  • bcl-X Protein
  • Sulfonamides
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Leukemia, Myeloid, Acute
  • Humans
  • Drug Resistance, Neoplasm
  • Cell Line, Tumor
  • Bridged Bicyclo Compounds, Heterocyclic
  • Antineoplastic Agents
 

Citation

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Lin, K. H., Winter, P. S., Xie, A., Roth, C., Martz, C. A., Stein, E. M., … Wood, K. C. (2016). Targeting MCL-1/BCL-XL Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia. Sci Rep, 6, 27696. https://doi.org/10.1038/srep27696
Lin, Kevin H., Peter S. Winter, Abigail Xie, Cullen Roth, Colin A. Martz, Elizabeth M. Stein, Gray R. Anderson, Jennifer P. Tingley, and Kris C. Wood. “Targeting MCL-1/BCL-XL Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia.Sci Rep 6 (June 10, 2016): 27696. https://doi.org/10.1038/srep27696.
Lin KH, Winter PS, Xie A, Roth C, Martz CA, Stein EM, et al. Targeting MCL-1/BCL-XL Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia. Sci Rep. 2016 Jun 10;6:27696.
Lin, Kevin H., et al. “Targeting MCL-1/BCL-XL Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia.Sci Rep, vol. 6, June 2016, p. 27696. Pubmed, doi:10.1038/srep27696.
Lin KH, Winter PS, Xie A, Roth C, Martz CA, Stein EM, Anderson GR, Tingley JP, Wood KC. Targeting MCL-1/BCL-XL Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia. Sci Rep. 2016 Jun 10;6:27696.

Published In

Sci Rep

DOI

EISSN

2045-2322

Publication Date

June 10, 2016

Volume

6

Start / End Page

27696

Location

England

Related Subject Headings

  • bcl-X Protein
  • Sulfonamides
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Leukemia, Myeloid, Acute
  • Humans
  • Drug Resistance, Neoplasm
  • Cell Line, Tumor
  • Bridged Bicyclo Compounds, Heterocyclic
  • Antineoplastic Agents