title: A personalised medicine approach for ponatinib-resistant chronic myeloid leukaemia.
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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Molecular Oncology Group.
authors.forename: K
authors.initials: K
authors.lastname: Korfi
authors.affiliation: Molecular Oncology Group.
authors.forename: A
authors.initials: A
authors.lastname: Mandal
authors.affiliation: Molecular Oncology Group.
authors.forename: S J
authors.initials: SJ
authors.lastname: Furney
authors.affiliation: Leukaemia Biology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: D
authors.initials: D
authors.lastname: Wiseman
authors.affiliation: Leukaemia Biology Group, Cancer Research UK Manchester Institute, University of Manchester, Manchester, UK.
authors.forename: T C P
authors.initials: TCP
authors.lastname: Somervaille
authors.affiliation: Molecular Oncology Group. Electronic address: richard.marais@cruk.manchester.ac.uk.
authors.forename: R
authors.initials: R
authors.lastname: Marais
mesh_terms: D000368:Aged; D000814:Aniline Compounds / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000235:genetics; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D058990:Molecular Targeted Therapy; D009154:Mutation; D057285:Precision Medicine; D011237:Predictive Value of Tests; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics; D011724:Pyridazines / Q000009:adverse effects / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use; D017211:Treatment Failure; D014407:Tumor Cells, Cultured
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; C000595707:BCL2 protein, human; C581634:BCR-ABL1 fusion protein, human; D014408:Biomarkers, Tumor; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011724:Pyridazines; D013449:Sulfonamides; C545373:ponatinib; D016044:Fusion Proteins, bcr-abl; C528561:navitoclax
keywords: BCR-ABL1 mutations; CML; mechanisms of resistance; personalised medicine; whole-genome sequencing