Imatinib resistance: the role of BCR-ABL dependent and BCR-ABL independent mechanisms in the loss of response to tyrosine kinase inhibitors
Disclosure : Research Support/P.I. Novartis, Merck SD, Schering Plough, Amgen, AIRC; Consultant Novartis, Bristol M.S., Merck SD, Wyeth, Nerviano MS. Presentation includes discussion of the following off-label use of a drug or medical device: Dasatinib, Nilotinib, Bosutinib, MK0457, PHA739358.
41 slide(s) – 00:19:24 – English – 2008-06-13
Targeted inhibition of the BCR-ABL kinase by imatinib has revolutionized the therapy of CML inducing high rates of complete haematological and cytogenetic responses in chronic phase CML patients. However, imatinib has proven less successful in treating CML advanced phases and Ph+ ALL. Many mechanisms of resistance have been described and the understanding of the considerable role of ABL-kinase-domain mutations as mediators of resistance to imatinib has encouraged the development of a second generation of tyrosine kinase inhibitors capable of inhibiting these mutant proteins. However, these mutations do not account for all cases of resistance and have a negligible role in the inability of TKIs to eradicate residual disease in most CML patients responding to imatinib and in Ph+ ALL in complete cytogenetic and good molecular remission. This implies that BCR-ABL independent factors such as the cellular context of BCR-ABL expression and stage of disease decisively control the evolution of imatinib resistance. More recently, attention has turned to the that alternative genetic aberrations, which synergize with BCR-ABL to enable leukemic self-renewal.