Resistance imatinib

Kopt Ta M, Falinski R, Nowicki MO et al. BCR/ABL kinase induces self-mutagenesis via reactive oxygen species to encode imatinib resistance. Blood 2006 108 319-327. 

These impressive results led to AMN107 being dubbed both Super Gleevec and Son of Gleevec. Phase II trials have been initiated and these continuing studies will determine if AMN107 will enter the market for not only the treatment of imatinib-resistant CML but perhaps replace imatinib as the first line agent. 

AG 1024 has been extensively studied as an IGFR inhibitor [70] and is a substrate competitive inhibitor of this kinase [71]. AG1024 also inhibits other kinases including c-Kit [72]. Additional studies will be needed, including a direct measurement of Abl activity and possible subsequent testing against the imatinib resistant Abl point mutations, to ascertain the possible therapeutic utility of AG 1024. 

Late in 2003 there were reports in CML patient newsletters about a new Src/Abl inhibitor from Bristol Myers Squibb (BMS) that was in clinical trials for the treatment of imatinib-resistant CML [123,124]. At the 2004 AACR meeting, there were three presentations on this new compound, BMS-354825 (32), although the structure was not disclosed at this time [125-127]. It was reported that BMS-354825 was 500-fold more potent than imatinib at inhibiting Abl kinase activity and that it was also effective against 14 out of 15 of the imatinib-resistant Abl mutations, with the exception being the T315I mutant. 

BCR-ABL Mutations and Imatinib Resistance in Chronic Myeloid Leukemia Patients... 

The number of mutations within the ABLl kinase domain of BCR-ABLl continues to grow rapidly, and it has recently been estimated that 73 distinct point mutations causing substitutions in 50 amino acids have been found in cells from imatinib-resistant CML patients, with some being more frequently found than others (Fig. 4). 

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