Molecular mechanism of TKI resistance and potential approaches to overcome resistance

There has been a remarkable improvement in the survival of patients with chronic myeloid leukaemia (CML) in chronic phase since the introduction of tyrosine kinase inhibitors (TKIs). However there are a significant proportion of patients with CML who are resistant to TKIs and are at risk of subsequent transformation to the accelerated and blast phases of CML, which are associated with poor survival. Further, while substantial response heterogeneity exists among patients treated with TKIs, almost all patients, including those with complete molecular remission, will continue to harbour quiescent leukaemic stem cells (LSCs). Although ABL1-kinase domain mutations that impair TKI activity have been linked to drug resistance and blastic transformation, more recent work has highlighted several genetic and epigenetic mechanisms dependent and independent of BCR-ABL1. Interesting interplays between LSCs and intracellular signalling pathways, as well as important contributions from the bone marrow microenvironment, have also been recently described. Several preclinical and clinical studies on combining new therapeutic targets with tyrosine kinase inhibitors are underway in efforts to overcome the problem of TKI resistance in CML.

Duke Scholars

Author Sin Tiong Ong Medicine, Medical Oncology