title: Bypass mechanisms of resistance to tyrosine kinase inhibition in chronic myelogenous leukaemia.
abstract: 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.
authors: Gabriella
authors: G
authors: Marfe
authors: Department of Biochemistry and Biophysics, Second University of Naples, via De Crecchio 7, Naples 80138, Italy. gabmarfe@alice.it.
authors: Carla
authors: C
authors: Di Stefano
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D013841:Thiazepines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013841:Thiazepines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl