Analysis of the Molecular Determinants of the Response of Chronic Myelogenous Leukaemia to Tyrosine Kinase Inhibitors

Helene      Labussiere; Sandrine      Hayette; Franck   E.   Nicolini

Abstract

The treatment of Chronic Myelogenous Leukaemia (CML) has been revolutionized by the introduction of Tyrosine Kinase Inhibitors (TKIs) and represents a new paradigm for the treatment of cancer. Imatinib Mesylate (IM) specifically targets limited numbers of tyrosine kinases (BCR-ABL, PDGFRα, PDGFRβ, C-ABL, c-fms and c-Kit), which explains its specific anti-tumoural efficacy and limited toxicity. In CML, the pivotal phase III trial has demonstrated the high superiority of IM for progression-free survival among interferon-α + cytarabine. Despite this remarkable success, > 90% of the patients show long-term persistence of limited numbers of malignant cells in their body raising the intriguing question of the persistence of BCR-ABL+ leukaemic stem cells serving as a reservoir for the disease. In addition, and maybe as a consequence, growing numbers of patients escape from IM-disease control and progressively or brutally relapse. Considerable progress has been made in understanding the mechanisms responsible for CML resistance to IM, and the onset of BCR-ABL oncogene point mutations remains the most frequent and investigated event in this setting. More than 50 mutations have been described in patients samples to date, which have a major impact on disease behavior and on the management of disease control. Interestingly, the prognosis seems quite different according to the type of mutations identified, and moreover particular mutations are more frequent in advanced phases of CML where their identification represents a marker of progression. Second generation TKIs have reached the level of clinical trials, and it is likely that they would overcome the majority of BCR-ABL mutation-induced resistances. However, some patients harbouring BCRABL mutations do not respond to these new compounds either, suggesting the onset of other molecular mechanisms involved in the resistance of the disease to TKIs. The aim of this review is to summarize the knowledge accumulated recently on the impact of BCR-ABL mutations in the sensitivity/resistance of CML to TKIs.

Keywords: CML, Philadelphia chromosome, BCR-ABL, tyrosine kinase inhibitors

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