Targeting MCL-1/BCL-XL Forestalls the Acquisition of Resistance to ABT-199 in Acute Myeloid Leukemia.
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.
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
Kevin H
KH
Lin
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.|Program in Genetics and Genomics, Duke University, Durham, NC 27710, USA.
Peter S
PS
Winter
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
Abigail
A
Xie
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.|Program in Genetics and Genomics, Duke University, Durham, NC 27710, USA.
Cullen
C
Roth
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
Colin A
CA
Martz
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
Elizabeth M
EM
Stein
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
Gray R
GR
Anderson
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
Jennifer P
JP
Tingley
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
Kris C
KC
Wood
D000970:Antineoplastic Agents / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D051020:bcl-X Protein / Q000235:genetics* / Q000378:metabolism
D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D019086:Bridged Bicyclo Compounds, Heterocyclic; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D013449:Sulfonamides; D051020:bcl-X Protein; C579720:venetoclax