Search: WFRF:(Borg M.)
> (2015-2019) >
Aberrant activation...
Aberrant activation of the PI3K/mTOR pathway promotes resistance to sorafenib in AML
-
- Lindblad, O (author)
- Lund University,Lunds universitet,Avdelningen för translationell cancerforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Division of Translational Cancer Research,Department of Laboratory Medicine,Faculty of Medicine,Stem Cell Center,Division of stem cell research,Skåne University Hospital
-
- Cordero, E (author)
- Lund University,Lunds universitet,Avdelningen för translationell cancerforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Translational Cancer Research,Department of Laboratory Medicine,Faculty of Medicine
-
- Puissant, A (author)
- Harvard University
-
show more...
-
Macaulay, L. (author)
-
- Ramos, A (author)
- Massachusetts Institute of Technology
-
- Kabir, N N (author)
- KN Biomedical Research Institute
-
- Sun, J (author)
- Lund University,Lunds universitet,Avdelningen för translationell cancerforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Division of Translational Cancer Research,Department of Laboratory Medicine,Faculty of Medicine,Stem Cell Center,Division of stem cell research
-
- Vallon-Christersson, J (author)
- Lund University,Lunds universitet,Sektion V,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Section V,Department of Clinical Sciences, Lund,Faculty of Medicine
-
- Haraldsson, K (author)
- Lund University,Lunds universitet,Sektion V,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Section V,Department of Clinical Sciences, Lund,Faculty of Medicine
-
- Hemann, M T (author)
- Massachusetts Institute of Technology
-
- Borg, Åke (author)
- Lund University,Lunds universitet,Sektion V,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Section V,Department of Clinical Sciences, Lund,Faculty of Medicine
-
- Levander, F (author)
- Lund University,Lunds universitet,Institutionen för immunteknologi,Institutioner vid LTH,Lunds Tekniska Högskola,Department of Immunotechnology,Departments at LTH,Faculty of Engineering, LTH
-
- Stegmaier, K (author)
- Harvard University
-
- Pietras, K (author)
- Lund University,Lunds universitet,Avdelningen för translationell cancerforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Division of Translational Cancer Research,Department of Laboratory Medicine,Faculty of Medicine
-
- Rönnstrand, L (author)
- Lund University,Lunds universitet,Avdelningen för translationell cancerforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Division of Translational Cancer Research,Department of Laboratory Medicine,Faculty of Medicine,Stem Cell Center,Division of stem cell research
-
- Kazi, J U (author)
- Lund University,Lunds universitet,Avdelningen för translationell cancerforskning,Institutionen för laboratoriemedicin,Medicinska fakulteten,Stamcellscentrum (SCC),Avdelningen för stamcellsforskning,Division of Translational Cancer Research,Department of Laboratory Medicine,Faculty of Medicine,Stem Cell Center,Division of stem cell research,KN Biomedical Research Institute
-
show less...
-
(creator_code:org_t)
- 2016-03-21
- 2016
- English 13 s.
-
In: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 35:39, s. 5119-5131
- Related links:
-
http://dx.doi.org/10... (free)
-
show more...
-
https://www.nature.c...
-
https://lup.lub.lu.s...
-
https://doi.org/10.1...
-
show less...
Abstract
Subject headings
Close
- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Publication and Content Type
- art (subject category)
- ref (subject category)
Find in a library
-
Oncogene
(Search for host publication in LIBRIS)
To the university's database
- By the author/editor
-
Lindblad, O
-
Cordero, E
-
Puissant, A
-
Macaulay, L.
-
Ramos, A
-
Kabir, N N
-
show more...
-
Sun, J
-
Vallon-Christers ...
-
Haraldsson, K
-
Hemann, M T
-
Borg, Åke
-
Levander, F
-
Stegmaier, K
-
Pietras, K
-
Rönnstrand, L
-
Kazi, J U
-
show less...
- About the subject
-
- MEDICAL AND HEALTH SCIENCES
-
MEDICAL AND HEAL ...
-
and Basic Medicine
-
and Cell and Molecul ...
- Articles in the publication
-
Oncogene
- By the university
-
Lund University