Resistance to imatinib: mutations and beyond

Mechanisms of resistance to the tyrosine kinase inhibitor (TKI) imatinib had been modeled in vitro even prior to the first reports of clinical resistance in patients with chronic myeloid leukemia (CML). The discovery that BCR-ABL is reactivated at the time of resistance and the unveiling of point mutations within the kinase domain of BCR-ABL as a major resistance mechanism have driven the development of second-generation TKIs. These agents are effective in a significant proportion of patients who fail to respond to imatinib. Clinical practice guidelines recommend using the BCR-ABL mutation genotype to aid selection of second-line treatment. Although kinase domain mutations are undoubtedly relevant to drug resistance, recent data suggest that additional resistance mechanisms must be operational in patients with and without kinase domain mutations. Clonal chromosomal evolution, BCR-ABL amplification, pharmacogenomic variations, or activation of signaling shortcuts have all been implicated in drug resistance, but their precise contributions to resistance remain to be determined. Additionally, lack of adherence to prescribed medication is likely to set the stage for resistance development. An area of intense research is primary resistance of leukemic stem cells (LSCs), which are thought to cause minimal residual disease to persist despite sustained treatment. The intent of this review is to shed light on the various aspects of TKI resistance in CML with respect to their biology and clinical implications.