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Computer simulations of the signalling network in FLT3+-acute myeloid leukaemia: indications for an optimal dosage of inhibitors against FLT3 and CDK6
Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. Università della Svizzera Italiana, Italy;Swiss Institute of Bioinformatics, Switzerland. (Ctr Biomat Chem;BMC;CCBG;EEMiS)ORCID iD: 0000-0002-6469-0296
Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. (Ctr Biomat Chem;BMC;CCBG)ORCID iD: 0000-0001-8696-3104
2018 (English)In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 19, p. 1-13, article id 155Article in journal (Refereed) Published
Abstract [en]

Background

Mutations in the FMS-like tyrosine kinase 3 (FLT3) are associated with uncontrolled cellular functions that contribute to the development of acute myeloid leukaemia (AML). We performed computer simulations of the FLT3-dependent signalling network in order to study the pathways that are involved in AML development and resistance to targeted therapies.

Results

Analysis of the simulations revealed the presence of alternative pathways through phosphoinositide 3 kinase (PI3K) and SH2-containing sequence proteins (SHC), that could overcome inhibition of FLT3. Inhibition of cyclin dependent kinase 6 (CDK6), a related molecular target, was also tested in the simulation but was not found to yield sufficient benefits alone.

Conclusions

The PI3K pathway provided a basis for resistance to treatments. Alternative signalling pathways could not, however, restore cancer growth signals (proliferation and loss of apoptosis) to the same levels as prior to treatment, which may explain why FLT3 resistance mutations are the most common resistance mechanism. Finally, sensitivity analysis suggested the existence of optimal doses of FLT3 and CDK6 inhibitors in terms of efficacy and toxicity.

Place, publisher, year, edition, pages
2018. Vol. 19, p. 1-13, article id 155
National Category
Bioinformatics and Systems Biology Biochemistry and Molecular Biology Cancer and Oncology
Research subject
Natural Science, Biomedical Sciences
Identifiers
URN: urn:nbn:se:lnu:diva-73804DOI: 10.1186/s12859-018-2145-yISI: 000431025900001PubMedID: 29699481OAI: oai:DiVA.org:lnu-73804DiVA, id: diva2:1203667
Funder
Swedish Cancer Society, CAN 2015/387Available from: 2018-05-04 Created: 2018-05-04 Last updated: 2018-07-11Bibliographically approved

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Buetti-Dinh, AntoineFriedman, Ran

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