Abl Tyrosine Kinase Inhibitors for Overriding Bcr-Abl/T315I
Treatment of chronic myeloid leukemia (CML) has changed drastically with the emergence of the Abl tyrosine kinase inhibitor (TKI), imatinib mesylate. However, primary and secondary resistance have frequently been reported, particularly in patients with advanced-stage disease. Point mutations within the Abl kinase domain that interfere with imatinib binding are the most critical cause of imatinib resistance. In order to override this resistance, several second generation ATP-competitive Abl TKIs including dasatinib, nilotinib, bosutinib and INNO-406 have been developed. Despite promising clinical results from these novel Abl TKIs for most mutations, the frequently observed mutant T315I is not effectively targeted by any of these agents. Thus, identification of novel agents and the development of new strategies for the effective treatment of CML patients with the T315I mutation are important and challenging tasks. In this review, the current status of novel agents for CML treatment is overviewed as follows: pathogenesis and features of CML; imatinib and second-generation Abl TKIs; why Abl TKIs are not effective against T315I; and novel agents that may override the T315I mutation.
Treatment for chronic myeloid leukemia (CML) has drastically changed with the emergence of the Abl tyrosine kinase inhibitor (TKI), imatinib mesylate (Glivec, Gleevec). However, a small percentage of patients in chronic phase (CP) and most advanced phase patients relapse on imatinib therapy. Imatinib-resistant mechanisms are Bcr–Abl-dependent or -independent. Bcr–Abl-dependent mechanisms of resistance to imatinib include the overexpression of Bcr–Abl and amplification of the bcr–abl gene, and, most intriguingly, point mutations within the Abl kinase domain that interfere with imatinib binding. Gorre et al. were the first to report that six of nine patients who lost responsiveness to imatinib demonstrated a single amino acid substitution in the threonine 315 residue to isoleucine (T315I) in the Abl kinase domain. To date, at least 90 different point mutations that encode distinct single amino-acid substitutions in the Bcr–Abl kinase domain have been isolated from relapsed CML patients who are resistant to imatinib. In order to override imatinib-resistance mechanisms, several second-generation Abl TKIs including dasatinib, nilotinib, bosutinib and INNO-406 have been developed. Despite promising clinical results from these novel Abl TKIs for most mutations, the frequently observed mutant T315I is not effectively targeted by any of these compounds. Thus, the identification of novel agents that are effective for T315I mutation is an important and challenging task.
Though allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important option as a curative treatment, the applicability of this method is greatly limited by its high toxicity and by donor limitations. Thus, we focus on the development of novel agents in this review to pursue a hope that it will be possible to safely cure CML patients without allo-HSCT.
Treatment of chronic myeloid leukemia (CML) has changed drastically with the emergence of the Abl tyrosine kinase inhibitor (TKI), imatinib mesylate. However, primary and secondary resistance have frequently been reported, particularly in patients with advanced-stage disease. Point mutations within the Abl kinase domain that interfere with imatinib binding are the most critical cause of imatinib resistance. In order to override this resistance, several second generation ATP-competitive Abl TKIs including dasatinib, nilotinib, bosutinib and INNO-406 have been developed. Despite promising clinical results from these novel Abl TKIs for most mutations, the frequently observed mutant T315I is not effectively targeted by any of these agents. Thus, identification of novel agents and the development of new strategies for the effective treatment of CML patients with the T315I mutation are important and challenging tasks. In this review, the current status of novel agents for CML treatment is overviewed as follows: pathogenesis and features of CML; imatinib and second-generation Abl TKIs; why Abl TKIs are not effective against T315I; and novel agents that may override the T315I mutation.
Treatment for chronic myeloid leukemia (CML) has drastically changed with the emergence of the Abl tyrosine kinase inhibitor (TKI), imatinib mesylate (Glivec, Gleevec). However, a small percentage of patients in chronic phase (CP) and most advanced phase patients relapse on imatinib therapy. Imatinib-resistant mechanisms are Bcr–Abl-dependent or -independent. Bcr–Abl-dependent mechanisms of resistance to imatinib include the overexpression of Bcr–Abl and amplification of the bcr–abl gene, and, most intriguingly, point mutations within the Abl kinase domain that interfere with imatinib binding. Gorre et al. were the first to report that six of nine patients who lost responsiveness to imatinib demonstrated a single amino acid substitution in the threonine 315 residue to isoleucine (T315I) in the Abl kinase domain. To date, at least 90 different point mutations that encode distinct single amino-acid substitutions in the Bcr–Abl kinase domain have been isolated from relapsed CML patients who are resistant to imatinib. In order to override imatinib-resistance mechanisms, several second-generation Abl TKIs including dasatinib, nilotinib, bosutinib and INNO-406 have been developed. Despite promising clinical results from these novel Abl TKIs for most mutations, the frequently observed mutant T315I is not effectively targeted by any of these compounds. Thus, the identification of novel agents that are effective for T315I mutation is an important and challenging task.
Though allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important option as a curative treatment, the applicability of this method is greatly limited by its high toxicity and by donor limitations. Thus, we focus on the development of novel agents in this review to pursue a hope that it will be possible to safely cure CML patients without allo-HSCT.
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