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Mechanisms resulting in imatinib-resistance can be subdivided into bcr-abl dependent and bcr-ab independent mechanisms. Bcr-abl dependent mechanisms include bcr-abl duplication and mutation. Bcr-abl duplication was the first mechanism of imatinib-resistance to be described. Gene duplication results in increased expression of the oncoprotein. Increasing dosages of imatinib can combat this effect, but frequently at the expense of intolerable adverse effects. The second bcr-abl dependent mechanism is via point mutations, which substitute amino acids within the kinase domain. Thus, the point mutations disrupt the binding site of imatinib on bcr-abl causing drug-resistance. The two most clinically important of the point mutations identified so far are the P-loop and T315I mutations. The T315I mutation is the substitution of an isoleucine for a threonine at position 315. The substitution results in the presence of a hydrophobic residue as opposed to a polar one at this position and totally disrupts the binding of imatinib. This mutation results in total resistance to imatinib as well as all second generation inhibitors known thus far. The P-loop mutation is the most common accounting for slightly less than 50% of all mutations to bcr-abl. The P-loop is the ATP-binding activation loop. When it is mutated, it is destabilized and the kinase cannot assume the inactive comformation that is required for imatinib binding. Bcr-abl independent mechanisms include increased drug efflux, decreased drug import, and alternative activation of bcr-abl downstream signaling pathways. Increased drug efflux is mostly due to increased expression of the P-glycoprotein efflux pump. In some cases, inhibitors of this protein have restored imatinib susceptibility. Decreased drug import is frequently due to mutations in the organic cation transporter (OCT1). Mutations in OCT1 decrease the concentrations of imatinib found intracellularly. Alternative signling pathway activation is typically mediated by the Src family kinases, which stabilize the active conformation of the bcr-abl kinase that cannot bind imatinib, thus inducing resistance. As understanding of these mechanisms of resistance increased, efforts began to focus on developing second generation drugs that will be more potent and less susceptible to resistance than imatinib. There are currently two second generation inhibitors that are in late phase clinical trials. Nilotinib is a derivative of imatinib. Changes were made to the imatinib structure to make it more specific as a bcr-abl inhibitor; the result was nilotinib. Nilotinib is 10-30 fold more potent than imatinib and has been shown to be effective even in the presence of all mutations causing imatinib resistance, except for T315I, even though it shares the same binding site as imatinib. Nilotinib is also effective against some bcr-abl independent mechanisms as it’s import into the cell is not dependent on OCT1 and it is not a substrate of the P-glycoprotein efflux pump. The other second generation drug in clinical trails is Dasatinib. Dasatinib was discovered by accident in a screen looking for immunosuppressive drugs. However, it has proven to be 325 fold more potent than imatinib in cells expressing bcr-abl. Dastinib inhibits not only bcr-abl, but also Src kinases and a number of downstream kinases. Therefore, dastinib, is effective in patients that are resistant to imatinib treatment due to alternative activation of downstream signaling. Like nilotinib, dasatinib is effective against all mutations leading to bcr-able resistance with the exception of T315I and is not targeted by the P-glycoprotein efflux pump. However, as dasatinib binds to abl at a novel site, the potential exists for novel mutations which will cause resistance to this new drug. Because new bcr-abl mutations which cause resistance to imatinib, but also potentially to these new second generation drugs, are still being discovered, efforts continue to develop drugs to treat patients with CML. New drugs currently being tested include Bosutinib, a fairly non-selective kinase inhibitor with greatest potency toward abl and src, Ponatinib, the first drug shown in preliminary studies to be effective against the T315I mutation, and Bafetinib, a very specific inhibitor of bcr-abl and the src kinases Lck and Lyn. Imatinib remains the first line of treatment in patients with CML. However, bcr-abl mutations rendering patients resistant to imatinib treatment are becoming more and more common. Efforts continue to develop new drugs that will be effective against imatinib-resistant CML. Two such drugs currently emerging from clinical trials onto the market are nilotinib and dasatinib. However, even as they are beginning to be used, mutations negating the effects of these drugs are being discovered. So, the drug discovery pipeline continues in search of new, more potent drugs, for treatment of CML. REFERNCES 1. Manley, P.; Cowan-Jacob, S.; Mestan, J. (2005). “Advances in the structural biology, design and clinical development of Bcr-Abl kinase inhibitors for the treatment of chronic myeloid leukaemia”. Biochimica et biophysica acta 1754 (1–2): 3–13. 2. Manley, P.; Stiefl, N.; Cowan-Jacob, S.; Kaufman, S.; Mestan, J.; Wartmann, M.; Wiesmann, M.; Woodman, R. et al. (2010). “Structural resemblances and comparisons of the relative pharmacological properties of imatinib and nilotinib”. Bioorganic & medicinal chemistry 18 (19): 6977–6986. 3. Jabbour, E., Cortes, J., Kantarjian, H. (2009). “Nilotinib for the treatment of chronic myeloid leukemia: An evidence-based review”. Core evidence 4: 207-213. 4. Olivieri, A.; Manzione, L. (2007). “Dasatinib: a new step in molecular target therapy”. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 18 Suppl 6: vi42–vi46. 5. Breccia, M.; Alimena, G. (2010). “Nilotinib: a second-generation tyrosine kinase inhibitor for chronic myeloid leukemia”. Leukemia research 34 (2): 129–134. 6. Boschelli, F.; Arndt, K.; Gambacorti-Passerini, C. (2010). “Bosutinib: a review of preclinical studies in chronic myelogenous leukaemia”. European journal of cancer (Oxford, England : 1990) 46 (10): 1781–1789. 7. O’Hare, T.; Pollock, R.; Stoffregen, E. P.; Keats, J. A.; Abdullah, O. M.; Moseson, E. M.; Rivera, V. M.; Tang, H. et al. (2004). “Inhibition of wild-type and mutant Bcr-Abl by AP23464, a potent ATP-based oncogenic protein kinase inhibitor: implications for CML”. Blood 104 (8): 2532–2539. 8. O’Hare, T.; Shakespeare, W.; Zhu, X.; Eide, C.; Rivera, V.; Wang, F.; Adrian, L.; Zhou, T. et al. (2009). “AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance”. Cancer cell 16 (5): 401–412. 9. Kimura, S.; Naito, H.; Segawa, H.; Kuroda, J.; Yuasa, T.; Sato, K.; Yokota, A.; Kamitsuji, Y. et al. (2005). “NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia”. Blood 106 (12): 3948–3954. 10. Horio, T.; Hamasaki, T.; Inoue, T.; Wakayama, T.; Itou, S.; Naito, H.; Asaki, T.; Hayase, H. et al. (2007). “Structural factors contributing to the Abl/Lyn dual inhibitory activity of 3-substituted benzamide derivatives”. Bioorganic & medicinal chemistry letters 17 (10): 2712–2717. 11. Deguchi, Y.; Kimura, S.; Ashihara, E.; Niwa, T.; Hodohara, K.; Fujiyama, Y.; Maekawa, T. (2008). “Comparison of imatinib, dasatinib, nilotinib and INNO-406 in imatinib-resistant cell lines”. Leukemia research 32 (6): 980–983. 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