Novel agents in CML therapy: tyrosine kinase inhibitors and beyond.
The emergence of resistance to imatinib has become a significant problem despite the remarkable clinical results achieved with this tyrosine kinase inhibitor in the treatment of chronic myeloid leukaemia. The most common cause of imatinib resistance is the selection of leukemic clones with point mutations in the Abl kinase domain. These mutations lead to amino acid substitutions and prevent the appropriate binding of imatinib. Genomic amplification of BCR-ABL, modulation of drug efflux or influx transporters, and Bcr-Abl-independent mechanisms also play important roles in the development of resistance. Persistent disease is another therapeutic challenge and may in part, be due to the inability of imatinib to eradicate primitive stem cell progenitors. A multitude of novel agents have been developed and have shown in vitro and in vivo efficacy in overcoming imatinib resistance. In this review, we will discuss the current status of the ATP-competitive and non-ATP-competitive Bcr-Abl tyrosine kinase inhibitors. We will also describe inhibitors acting on targets found in signaling pathways downstream of Bcr-Abl, such as the Ras-Raf-mitogen-activated protein kinase and phosphatidylinositol-3 kinase-Akt-mammalian target of rapamycin pathways, and targets without established links with Bcr-Abl.
Melo
Junia V
JV
Division of Haematology, Institute of Medical & Veterinary Science, Adelaide SA, Australia. junia.melo@imvs.sa.gov.au
Chuah
Charles
C
D000814:Aniline Compounds / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000627:therapeutic use; D001549:Benzamides; D002986:Clinical Trials as Topic; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D005784:Gene Amplification; D006248:Harringtonines / Q000627:therapeutic use; D056572:Histone Deacetylase Inhibitors; D000077863:Homoharringtonine; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D009570:Nitriles / Q000627:therapeutic use; D010087:Oxides / Q000627:therapeutic use; D010879:Piperazines / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000627:therapeutic use*; D011804:Quinolines / Q000627:therapeutic use; D013844:Thiazoles / Q000627:therapeutic use
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D001152:Arsenicals; D001549:Benzamides; D004791:Enzyme Inhibitors; D006248:Harringtonines; D056572:Histone Deacetylase Inhibitors; D009570:Nitriles; D010087:Oxides; D010879:Piperazines; D011743:Pyrimidines; D011804:Quinolines; D013844:Thiazoles; C471992:bosutinib; D000077863:Homoharringtonine; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib; D000077237:Arsenic Trioxide