Oncotarget

Research Papers:

An erratum has been issued for this paper. Erratum in: Oncotarget. 2020; 11:305-305.

PTEN deletion drives acute myeloid leukemia resistance to MEK inhibitors

Amanda M. Smith, Christine R.C. Zhang, Alexandre S. Cristino, John P. Grady, J. Lynn Fink _ and Andrew S. Moore _

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Oncotarget. 2019; 10:5755-5767. https://doi.org/10.18632/oncotarget.27206

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Abstract

Amanda M. Smith1,4,*, Christine R.C. Zhang1,4,*, Alexandre S. Cristino1,6, John P. Grady1,5, J. Lynn Fink1 and Andrew S. Moore1,2,3,4

1 The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Australia

2 Oncology Services Group, Queensland Children’s Hospital, South Brisbane, Australia

3 Child Health Research Centre, The University of Queensland, South Brisbane, Australia

4 Current address: Washington University in Saint Louis, Saint Louis, Missouri, United States of America

5 Current address: Garvan Institute of Medical Research, Darlinghurst, Australia

6 Current address: Griffith Institute for Drug Discovery, Brisbane Innovation Park, Nathan, Australia

* These authors contributed equally to this work

Correspondence to:

Andrew S. Moore,email: [email protected]
J. Lynn Fink,email: [email protected]

Keywords: myeloid leukemia; therapy; drug resistance; hematological malignancies; gene mutation

Abbreviations: MEKi: MEK inhibitor(s); TR: THP-1 cells with resistance to AZD6244

Received: January 30, 2019     Accepted: August 12, 2019     Published: October 08, 2019

ABSTRACT

Kinases such as MEK are attractive targets for novel therapy in cancer, including acute myeloid leukaemia (AML). Acquired and inherent resistance to kinase inhibitors, however, is becoming an increasingly important challenge for the clinical success of such therapeutics, and often arises from mutations in the drug-binding domain of the target kinase. To identify possible causes of resistance to MEK inhibition, we generated a model of resistance by long-term treatment of AML cells with AZD6244 (selumetinib). Remarkably, resistance to MEK inhibition was due to acquired PTEN haploinsufficiency, rather than mutation of MEK. Resistance via this mechanism was confirmed using CRISPR/Cas9 technology targeting exon 5 of PTEN. While PTEN loss has been previously implicated in resistance to a number of other therapeutic agents, this is the first time that it has been shown directly and in AML.


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