What does the future of molecularly based CML therapy hold? Although imatinib is a remarkably effective treatment for chronic phase CML, imatinib resistance does occur, particularly in blast crisis patients and usually as a result of mutations in BCR-ABL, in particular the prevalent Thr315Ile (T315I) mutation (100
). This has led to efforts to develop second generation BCR-ABL inhibitors that can block the activity of these imatinib-resistant mutant forms of BCR-ABL. In clinical trials, dasatanib, a c-Src and c-Abl inhibitor, proved effective in CML therapy and works against most of the imatinib-resistant BCR-ABL mutations, but not against Thr315Ile (102
). In June 2006, dasatanib (also known as Sprycel) was approved by the FDA for the treatment of patients with CML who showed resistance or intolerance to prior therapy. Nilotinib (also known as Tasigna), a derivative of imatinib that is also active against most of the imatinib-resistant mutations, but not against Thr315Ile BCR-ABL, has also shown promising results in clinical trials for CML and is expected to be approved soon.
The emergence of resistance to kinase inhibitors used in cancer therapy is a general phenomenon, and this has led to the development of methods to try and predetermine which mutations are likely to cause resistance (e.g., random PCR-based mutagenesis of BCR-ABL and expression in myeloid cell lines, followed by selection of imatinib-resistant cells in culture; ref. 103
). An understanding of the basis of imatinib resistance has come from the elegant structural analysis of imatinib bound to the c-ABL catalytic domain (104
), which helps explain how mutations distant from the residues that contact imatinib can induce resistance. The structures of these complexes also reveal how inhibitor specificity is achieved, and they have been important in the development of the second-generation BCR-ABL inhibitor nilotinib, in which the imatinib scaffold has been modified based on structural insights (105
). Methods have also been developed to identify existing kinase inhibitors that have already been evaluated in clinical trials and that might target the imatinib-resistant BCR-ABL mutants; the aurora kinase inhibitor, VX680, is a compound of this sort (107
) and is being tested clinically for the treatment of CML.
Because BCR-ABL inhibitor therapy generally only provides temporary remission in blast crisis CML patients, trials are underway to treat relapsed CML patients using a BCR-ABL kinase inhibitor in combination with other therapeutic modalities. Interestingly, a combination of imatinib and dasatinib seems to be more effective than either alone as primary treatment. Perhaps Src family kinases play an important role in acute phase CML; if so, the ability of dasatinib to inhibit both Src and Abl would then explain why this combination is more effective. Ideally one would like to design combination therapy on a more rational basis, but for this we need a better understanding of the molecular basis of late-stage disease. Like other cancers, CML is thought to be a stem cell–driven disease, and the true target cell that initiates CML may be a granulocyte-macrophage–like progenitor cell (109
). The ability to isolate leukemic stem cells from CML patients has begun to lead to a mechanistic understanding of the self-renewal and leukemic properties of these cells, which might be due to activation of the β-catenin pathway (109
). However, the key substrates for BCR-ABL phosphorylation that are important for stem cell renewal and the enhanced proliferation of their derivatives are still largely unknown. Many proteins phosphorylated by BCR-ABL have been identified, with recent phosphoproteomic analyses revealing that there are literally hundreds of tyrosine phosphorylated proteins in CML cells dependent on BCR-ABL activity (110
), and it will be a challenge to decipher how many of these tyrosine phosphorylation events, and in which combinations, are critical for CML. A knowledge of which signaling pathways are crucial might be useful in devising combinatorial therapies with different signal transduction inhibitors. In this regard, there is some evidence that targeting a second kinase, such as c-KIT, in addition to BCR-ABL (112
), might be necessary for effective treatment of CML. Imatinib happens to fulfill this requirement, and this might explain the effectiveness of this drug in the treatment of CML.
Finally, imatinib was developed with short-term therapy in mind and was not tested for prolonged use. Yet its very success in treating the chronic phase of CML has led to its continued administration over years rather than weeks or months. In fact, the first patients have been on imatinib for 6 years, with surprisingly few adverse consequences. Nevertheless, as new CML drugs are developed and success at obtaining lasting remission is achieved, it is important to consider the long-term effects of administering these compounds, particularly if used in combination with other drugs.