Send to

Choose Destination
Oncogene. 2016 Sep 29;35(39):5119-31. doi: 10.1038/onc.2016.41. Epub 2016 Mar 21.

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

Author information

Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden.
Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden.
Department of Hematology and Vascular Disorders, Skåne University Hospital, Lund, Sweden.
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Laboratory of Computational Biochemistry, KN Biomedical Research Institute, Barisal, Bangladesh.
Department of Oncology and Pathology, Lund University, Lund, Sweden.
Bioinformatics Infrastructure for Life Sciences (BILS), Department of Immunotechnology, Lund University, Lund, Sweden.


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.

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center