New Bcr-Abl inhibitors in chronic myeloid leukemia: keeping resistance in check

作者：O'Hare Thomas; Eide Christopher A; Deininger Michael W^*

来源：Expert Opinion on Investigational Drugs, 2008, 17(6): 865-878.

DOI：10.1517/13543780802121777

• Abl kinase inhibitor
• compound mutation
• dasatinib
• imatinib
• nilotinib

Targeted therapy with the Abl kinase inhibitor imatinib has markedly improved the outlook for patients with chronic myeloid leukemia (CML). Breakpoint cluster region (Bcr)-Abl signaling is reactivated at the time of resistance, predominantly due to mutations in the kinase domain of Bcr-Abl that interfere with drug binding. This discovery prompted the development of new Abl kinase inhibitors, among which nilotinib and dasatinib have gained regulatory approval. Despite excellent results in patients with imatinib-resistant or imatinib-intolerant CML treated with nilotinib or dasatinib, early indications suggest that: the cross-resistant Bcr-Abl(T3151) mutant is disproportionately represented among patients who relapse on these therapies; each Abl inhibitor exhibits vulnerabilities to certain kinase domain mutations. We review new inhibitors of Bcr-Abl, including preliminary information on inhibitors of Bcr-Abl(T3151) and discuss the potential of combined AN kinase inhibitor therapy to pre-empt resistance. Improved Abl inhibitor therapies will be useful in achieving maximum disease control but a clinical T3151 inhibitor remains a high priority.

• 出版日期2008-6