Molecular pathogenesis of tyrosine kinase resistance in chronic myeloid leukemia.
OBJECTIVE
The molecular pathogenesis of resistance against tyrosine kinase inhibitors imatinib, nilotinib, or dasatinib in patients treated for chronic myeloid leukemia is best understood based on mutations within the ABL-kinase domain. However, in about 50% of patients, clinical resistance so far cannot be linked to known mutations. Mutation-independent resistance development is imparted by a multifactorial array of mechanisms. The purpose of this review is to summarize recent publications on molecular mechanisms that govern the development of clinical resistance. Studies on the second-line inhibitors dasatinib and nilotinib addressing clinical efficacy in the presence of preexisting kinase mutations have largely confirmed the in-vitro prediction. With regard to mutation-independent resistance, new insights into the multifactorial resistance regulation were gained. Preclinical and clinical findings have revitalized the interest in interferon-alpha as a potentially useful adjunct for tyrosine kinase inhibitor-based treatment. The dogma of continuous kinase inhibition necessary for optimal efficacy has been challenged by clinical and preclinical data.


CONCLUSIONS
Elucidation of the complexity of resistance development most likely will help to preempt evolution of resistant disease. Clinical studies now focus on dose modifications, drug scheduling, optimized inhibitors, and drug combinations aiming to prevent resistance development.
La Rosée
Paul
P
Klinik für Innere Medizin II, Hämatologie/Onkologie, Universitätsklinikum Jena, Jena, Germany.
Hochhaus
Andreas
A
D001549:Benzamides; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D019143:Evolution, Molecular; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D009154:Mutation; D010879:Piperazines / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000627:therapeutic use*
D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases