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Oncotarget. 2019 Oct 8;10(56):5755-5767. doi: 10.18632/oncotarget.27206. eCollection 2019 Oct 8.

PTEN deletion drives acute myeloid leukemia resistance to MEK inhibitors.

Author information

The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Australia.
Current address: Washington University in Saint Louis, Saint Louis, Missouri, United States of America.
Current address: Griffith Institute for Drug Discovery, Brisbane Innovation Park, Nathan, Australia.
Current address: Garvan Institute of Medical Research, Darlinghurst, Australia.
Oncology Services Group, Queensland Children's Hospital, South Brisbane, Australia.
Child Health Research Centre, The University of Queensland, South Brisbane, Australia.
Contributed equally


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.


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

Conflict of interest statement

CONFLICTS OF INTEREST The authors declare no potential conflicts of interest.

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