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Aberrant activation of the PI3K/mTOR pathway promotes resistance to sorafenib in AML

Author:
  • O Lindblad
  • E Cordero
  • A Puissant
  • L. Macaulay
  • A Ramos
  • N N Kabir
  • J Sun
  • J Vallon-Christersson
  • K Haraldsson
  • M T Hemann
  • Åke Borg
  • F Levander
  • K Stegmaier
  • K Pietras
  • L Rönnstrand
  • J U Kazi
Publishing year: 2016-09-29
Language: English
Pages: 5119-5131
Publication/Series: Oncogene
Volume: 35
Issue: 39
Document type: Journal article
Publisher: Nature Publishing Group

Abstract english

Therapy directed against oncogenic FLT3 has been shown to induce response in patients with acute myeloid leukemia (AML), but these responses are almost always transient. To address the mechanism of FLT3 inhibitor resistance, we generated two resistant AML cell lines by sustained treatment with the FLT3 inhibitor sorafenib. Parental cell lines carry the FLT3-ITD (tandem duplication) mutation and are highly responsive to FLT3 inhibitors, whereas resistant cell lines display resistance to multiple FLT3 inhibitors. Sanger sequencing and protein mass-spectrometry did not identify any acquired mutations in FLT3 in the resistant cells. Moreover, sorafenib treatment effectively blocked FLT3 activation in resistant cells, whereas it was unable to block colony formation or cell survival, suggesting that the resistant cells are no longer FLT3 dependent. Gene expression analysis of sensitive and resistant cell lines, as well as of blasts from patients with sorafenib-resistant AML, suggested an enrichment of the PI3K/mTOR pathway in the resistant phenotype, which was further supported by next-generation sequencing and phospho-specific-antibody array analysis. Furthermore, a selective PI3K/mTOR inhibitor, gedatolisib, efficiently blocked proliferation, colony and tumor formation, and induced apoptosis in resistant cell lines. Gedatolisib significantly extended survival of mice in a sorafenib-resistant AML patient-derived xenograft model. Taken together, our data suggest that aberrant activation of the PI3K/mTOR pathway in FLT3-ITD-dependent AML results in resistance to drugs targeting FLT3.Oncogene advance online publication, 21 March 2016; doi:10.1038/onc.2016.41.

Keywords

  • Cell and Molecular Biology

Other

Published
  • ISSN: 1476-5594
Kristian Pietras
E-mail: kristian [dot] pietras [at] med [dot] lu [dot] se

Professor

Division of Translational Cancer Research

+46 46 222 64 29

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Project manager

Experimental oncology