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, Andrew S. Moore

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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.

Original languageEnglish
Pages (from-to)5755-5767
Number of pages13
JournalOncotarget
Volume10
Issue number56
DOIs
StatePublished - Oct 1 2019

Keywords

  • Drug resistance
  • Gene mutation
  • Hematological malignancies
  • Myeloid leukemia
  • Therapy

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