Editors' ChoiceChronic Myeloid Leukemia

Stopping a Mutant Kinase in Its Tracks

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Science Translational Medicine  02 Dec 2009:
Vol. 1, Issue 9, pp. 9ec34
DOI: 10.1126/scitranslmed.3000671

The "Philadelphia" chromosome—formed when segments of chromosomes 9 and 22 swap places—was the first genetic abnormality linked to cancer, when nearly 50 years ago two scientists associated this defect with chronic myeloid leukemia (CML). The chromosomal translocation, named after the city in which it was discovered, fuses the BCR gene with the tyrosine kinase-encoding ABL gene, resulting in the production of a hyperactive BCR-ABL fusion protein. BCR-ABL promotes proliferation of white blood cells, causing the early chronic phase of CML, which without treatment progresses to a disease resembling acute leukemia. The chronic phase can often be effectively treated with the ABL kinase inhibitor imatinib (Gleevec). Because some patients develop resistance to imatinib, however, usually as a result of point mutations in the BCR-ABL kinase domain, the drug must sometimes be discontinued. Two other ABL inhibitors, nilotinib (Tasigna) and dasatinib (Sprycel), are effective second-line therapies. But one kinase domain mutation—BCR-ABLT315I—causes resistance to all three drugs, which form a key hydrogen bond with the residue affected by the mutation. In mutant proteins that carry the T315I change, this crucial interaction is eliminated. To address this issue, O'Hare et al. sought to design inhibitors that bind to the ABL kinase domain, but not via the key hydrogen bond. One compound, AP24534, fit the bill. AP24534 inhibited the activity of the T315I mutant, as well as the native and other mutant forms of BCR-ABL in biochemical and cell growth assays and suppressed tumor growth driven by BCR-ABLT315I in mice. AP24534 also prevented the growth of drug-resistant clones in a cell-based assay, indicating that it might be useful, not only in patients with BCR-ABLT315I, but as a first-line drug for treating CML.

T. O'Hare et al., AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell 16, 401–412 (2009). [Abstract]

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