Mechanisms and novel approaches in overriding tyrosine kinase inhibitor resistance in chronic myeloid leukemia

Abstract

Chronic myeloid leukemia is a stem cell-initiated but progenitor-driven disease induced by the BCR–ABL oncogene. Tyrosine kinase inhibitors (TKIs) were introduced in the late 1990s and have revolutionized the management of chronic myeloid leukemia in chronic phase. The majority of patients can now expect to live a normal life as long as they continue to comply with TKI treatment. However, in a significant proportion of cases TKI resistance develops over time, requiring a switch of therapy. The most frequent mechanism for drug resistance is the development of kinase domain mutations that reduce or completely ablate drug efficacy. Fortunately, the last 10 years have seen an impressive array of new drugs, some modeled on the mechanism of action of imatinib, others employing more novel approaches, for these patients.

Keywords::

• BCR–ABL
• CML
• drug resistance
• kinase domain
• leukemia
• leukemic stem cell
• mutation
• Philadelphia chromosome
• T315I
• tyrosine kinase inhibitor

Financial & competing interests disclosure

M Karvela is funded by a University of Glasgow PhD studentship and GV Helgason by a Kay Kendall Leukaemia Fund project grant (KKL404). This work was funded by a Medical Research Council TSCRC (G0900882) grant and a Cancer Research UK program (C11074/A11008) grant. TL Holyoake has received funds and consultancy fees from Novartis, BMS and ChemGenex. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.