A personalised medicine approach for ponatinib-resistant chronic myeloid leukaemia.
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
BACKGROUND: Chronic myeloid leukaemia (CML) is characterised by the presence of a fusion driver oncogene, BCR-ABL1, which is a constitutive tyrosine kinase. Tyrosine kinase inhibitors (TKIs) are the central treatment strategy for CML patients and have significantly improved survival rates, but the T315I mutation in the kinase domain of BCR-ABL1 confers resistance to all clinically approved TKIs, except ponatinib. However, compound mutations can mediate resistance even to ponatinib and remain a clinical challenge in CML therapy. Here, we investigated a ponatinib-resistant CML patient through whole-genome sequencing (WGS) to identify the cause of resistance and to find alternative therapeutic targets. PATIENTS AND METHODS: We carried out WGS on a ponatinib-resistant CML patient and demonstrated an effective combination therapy against the primary CML cells derived from this patient in vitro. RESULTS: Our findings demonstrate the emergence of compound mutations in the BCR-ABL1 kinase domain following ponatinib treatment, and chromosomal structural variation data predicted amplification of BCL2. The primary CD34(+) CML cells from this patient showed increased sensitivity to the combination of ponatinib and ABT-263, a BCL2 inhibitor with a negligible effect against the normal CD34(+) cells. CONCLUSION: Our results show the potential of personalised medicine approaches in TKI-resistant CML patients and provide a strategy that could improve clinical outcomes for these patients.
Date Issued
2015-01-01
Date Acceptance
2015-02-17
Start Page
1180
End Page
1187
Journal / Book Title
Ann Oncol
Volume
26
Issue
6
Copyright Statement
© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.or
g/licenses/by-nc/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re
-use, please contact
journals.permissions@oup.com
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.or
g/licenses/by-nc/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re
-use, please contact
journals.permissions@oup.com
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/25712455
mdv110
Subjects
BCR-ABL1 mutations
CML
mechanisms of resistance
personalised medicine
whole-genome sequencing
Aged
Aniline Compounds
Antineoplastic Agents
Antineoplastic Combined Chemotherapy Protocols
Biomarkers, Tumor
DNA Mutational Analysis
Drug Resistance, Neoplasm
Drug Screening Assays, Antitumor
Fusion Proteins, bcr-abl
Genome-Wide Association Study
Humans
Imidazoles
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Molecular Targeted Therapy
Mutation
Precision Medicine
Predictive Value of Tests
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-bcl-2
Pyridazines
Sulfonamides
Treatment Failure
Tumor Cells, Cultured
1112 Oncology And Carcinogenesis
Oncology & Carcinogenesis
Publication Status
Published
Coverage Spatial
England