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The catalytic activity of Abl1 single and compound mutations: Implications for the mechanism of drug resistance mutations in chronic myeloid leukaemia
Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. (Linnaeus Ctr Biomat Chem, BMC;CCBG)ORCID iD: 0000-0003-4573-8052
Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. (Linnaeus Ctr Biomat Chem, BMC;CCBG)
Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences.ORCID iD: 0000-0002-9300-614X
Linnaeus University, Faculty of Health and Life Sciences, Department of Chemistry and Biomedical Sciences. (Linnaeus Ctr Biomat Chem, BMC;CCBG)ORCID iD: 0000-0001-8696-3104
2019 (English)In: Biochimica et Biophysica Acta - General Subjects, ISSN 0304-4165, E-ISSN 1872-8006, Vol. 1863, no 4, p. 732-741Article in journal (Refereed) Published
Abstract [en]

Background

Abl1 is a protein tyrosine kinase whose aberrant activation due to mutations is the culprit of several cancers, most notably chronic myeloid leukaemia. Several Abl1 inhibitors are used as anti-cancer drugs. Unfortunately, drug resistance limits their effectiveness. The main cause for drug resistance is mutations in the kinase domain (KD) of Abl1 that evolve in patients. The T315I mutation confers resistance against all clinically-available inhibitors except ponatinib. Resistance to ponatinib can develop by compound (double) mutations.

Methods

Kinetic measurements of the KD of Abl1 and its mutants were carried out to examine their catalytic activity. Specifically, mutants that lead to drug resistance against ponatinib were considered. Molecular dynamics simulations and multiple sequence analysis were used for explanation of the experimental findings.

Results

The catalytic efficiency of the T315I pan-resistance mutant is more than two times lower than that of the native KD. All ponatinib resistant mutations restore the catalytic efficiency of the enzyme. Two of them (G250E/T315I and Y253H/E255V) have a catalytic efficiency that is more than five times that of the native KD.

Conclusions

The measurements and analysis suggest that resistance is at least partially due to the development of a highly efficient kinase through subsequent mutations. The simulations highlight modifications in two structurally important regions of Abl1, the activation and phosphate binding loops, upon mutations.

General significance

Experimental and computational methods were used together to explain how mutations in the kinase domain of Abl1 lead to resistance against the most advanced drug currently in use to treat chronic myeloid leukaemia.

Place, publisher, year, edition, pages
Elsevier, 2019. Vol. 1863, no 4, p. 732-741
National Category
Biophysics Theoretical Chemistry Biochemistry and Molecular Biology
Research subject
Natural Science, Biomedical Sciences; Natural Science, Chemistry; Chemistry, Biochemistry
Identifiers
URN: urn:nbn:se:lnu:diva-80308DOI: 10.1016/j.bbagen.2019.01.011ISI: 000460853200009PubMedID: 30684523Scopus ID: 2-s2.0-85060896659OAI: oai:DiVA.org:lnu-80308DiVA, id: diva2:1286761
Funder
Swedish Cancer Society, CAN 2015/387Available from: 2019-02-07 Created: 2019-02-07 Last updated: 2019-08-29Bibliographically approved

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Georgoulia, Panagiota S.Todde, GuidoBjelic, SinisaFriedman, Ran

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