include cytoplasmic tyrosine kinase Bcr Abl in chronic myeloid leukemia, receptor tyrosine kinase KIT in systemic mastocytosis and gastrointestinal stromal tumors, and PDGFRa in hypereosinophilic syndrome. In 2001, SU11274 c-Met inhibitor the approval of Gleevec by FDA initiated a revolutionary targeted therapy against cancer with small molecule tyrosine kinase inhibitors. Gleevec blocks the signaling pathway of tyrosine kinase by competitively occupying the ATP binding pocket of Bcr Abl, KIT and PDGFRa, and therefore kills these oncogene addicted tumor cells. Patients with CML and HES have gained much better prognosis with the treatment of Gleevec. However, in some patients, relapse due to resistance to Gleevec is an emerging problem. Acquired point mutations within the target genes are a major mechanism of resistance to Gleevec in some patients with hematologic malignance.
The mutations are believed to block the binding of Gleevec to ATP binding pockets of these tyrosine buy LY294002 kinases. In this case, novel tyrosine kinase inhibitor such as nilotinib and dasatinib have been shown activity against Gleevec resistant patients bearing some point mutations but the gate keeper mutations. Therefore, development of more novel small molecule tyrosine kinase inhibitors is still needed. This talk covered the advance in the field of overcoming Gleevec resistance in terms of novel compounds and strategeies. Pan J et al reported that EXEL 0862 is effective against Gleevec resistant D816V KIT and T674I PDGFRa. Recently, in vitro and animal data supported that several novel tyrosine kinase inhibitors including AP24534 and DCC 2036 have been demonstrated effective against T315I Bcr Abl.
However, the efficacy and safety of these pounds in patients remains to be defined. An alternative approach for overcoming Gleevec resistance is to decrease the expression of addicted oncogenes, which are driving forces of the tumor cells, to kill the malignant cells. Our group discovered several compounds which are effective against Gleevec resistant tumor cells regardless of resistance to imatinib. The compounds kill cells harboring gate keeper mutants of tyrosine kinases by lowering the expression of the oncoproteins. Examples include triptolide, pristimerin and SNS 032, homoharringtonine, and celastrol. In summary, Gleevec resistance remains a challenge in leukemia.
The findings from us and others suggest that several aforementioned compounds are promising agents to overcome Gleevec resistance, and warrant clinical trials. Recent years have seen dramatic advances in deciphering the molecular pathogenesis of chronic myeloid leukemia. This has resulted in the rapid development of many BCR ABL1 specific tyrosine kinase inhibitors which have improved 10 year survival to more than 80%. In this paper we focus on some future directions for CML biology and therapy. Targeting CML stem cells Work from Tessa Holyoake,s lab in Glasgow showed that the majority of CML progenitor cells undergo division in culture in the presence of growth factors.1 When imatinib, nilotinib or dasatinib were added to the culture, the proliferating cells were killed while cells that do not divide were completely refractory to the drugs.2 These dormant or quiescent cells are probably responsible for,molecular persistence, namely, the residual low level of BCR ABL1 transcript positivity detected by quantitative PCR in many cases. Si