Kinase imatinib resistance

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. 

Abstract The hallmark of chronic myelogenous leukemia (CML) is the expression of Bcr-Abl, a constitutively active form of the Abl tyrosine kinase. Imatinib, a 2-phenylamino-pyrimidine Bcr-Abl inhibitor developed by Novartis and marketed under the tradename of Gleevec (Glivec), is highly effective in treating CML patients with early stage disease. However, patients with advanced disease often become resistant to imatinib. The predominant form of this resistance is the development of mutations in the Bcr-Abl protein. These point mutations can be amino acid residues that make direct contact with imatinib or residues that do not allow Bcr-Abl to adopt the inactive conformation. Since imatinib can only bind to the inactive conformation of the protein, both types of mutations prevent this inhibitor from binding. Several approaches have been taken to identify additional... 

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. 

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). 

Yamamoto M, Kurosu T, Kakihana K et al. The two major imatinib resistance mutations, E255K and T3151, enhance the activity of BCR/ABL fusion kinase. Biochem Biophys Res Commun 2004 319 1272-1275. 

Shah NP, Tran C, Lee FY et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004 305 399 01. 

Tokarski JS, Newitt JA, Chang CY et al. The strueture of Dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory aetivity against imatinib-resistant ABL mutants. Cancer Res 2006 66 5790-5797. 

O Hare T, Walters DK, Stoffregen EP et al. In vitro activity of BCR-ABL inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant ABL kinase domain mutants. Cancer Res 2005 65 4500 505. 

Kantarjian H, Gattermann N, Hochhaus A et al. A phase II study of nilotinib a novel tyrosine kinase inhibitor administered to imatinib-resistant or intolerant patients with ehronie myelogenous leukemia (CML) in aeeelerated phase (AP) (Abstraet 2169). Blood2006 108 615a. 

Imatinib (2),5 marketed by Novartis since 2001, is the first tyrosine kinase inhibitor approved as a treatment for chronic myelogenous leukemia (CML). It inhibits the BCR-ABL kinase that is highly specific to leukemic cells. Dasatinib (3)6 and nilotinib (4)7 are two other BCR-ABL kinase inhibitors marketed by Bristol-Myers Squibbs and Novartis, respectively. They are effective for the treatment of imatinib-resistant CML patients. 

Sunitinib (7),10 developed by Sugene/Pfizer, was approved in 2006 for the treatment of renal cell carcinoma (RCC). It is a VEGFR kinase inhibitor that slows down the angiogenesis of tumor endothelial cells, which provide nutrients and help tumor growth and metastasis. Sunitinib also blocks KIT, an oncogenic kinase that causes gastrointestinal stromal cell tumors. It was approved as a second-line anti-GSIT therapy for imatinib-resistant patients. 

Fig. 13.2 Imatinib wrapping modification engineered to overcome drug resistance in the C-Kit kinase. This resistance is promoted by the somatic mutation Asp816Val. The mutation induces the dehydron Phe811-Ala814 in the activation loop which in turn can be targeted or wrapped by suitably modifying imatinib at the position highlighted by the rectangle [3]...

The first kinase inhibitor to be developed for clinical use was imatinib 42, first marketed in 2001 for chronic myelogenous leukemia (CML). The clinical effectiveness of imatinib for the treatment of CML is now thought to be due to its multi-kinase activity, inhibiting PDGFR and c-KIT, in addition to its well known activity as a Bcr-Abl kinase inhibitor. Resistance to imatinib can become a problem due to mutations in the Abl gene. Dual Src/Abl inhibitors are currently of interest for the treatment of CML... 

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