Bypass Mechanisms of Resistance to Tyrosine Kinase Inhibition in Chronic Myelogenous Leukaemia
Gabriella Marfe and Carla Di Stefano
Affiliation: Department of Biochemistry and Biophysics, Second University of Naples, via De Crecchio 7, Naples 80138, Italy.
Chronic myeloid leukaemia (CML) is a disease induced by the BCR-ABL oncogene. Tyrosine kinase inhibitors
(TKIs) were introduced in the late 1990s and have revolutionized the management of CML. The majority of such patients
can now expect to live a normal life providing they continue to comply with TKI treatment. However, in a significant
proportion of cases, TKI resistance develops over time, requiring a change of therapy. Over the past few years, multiple
molecular mechanisms of resistance have been identified and some common themes have emerged. One is the development
of resistance mutations in the drug target that prevent the drug from effectively inhibiting the respective TK domain.
The second is activation of alternative molecules that maintain the signalling of key downstream pathways despite
sustained inhibition of the original drug target.
In this mini-review, we summarize the concepts underlying resistance, the specific examples known to date and the challenges
of applying this knowledge to develop improved therapeutic strategies to prevent or overcome resistance.
Keywords: Apoptosis, CML, imatinib, mTOR pathway, PBTDs.
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