Imatinib-resistant gastrointestinal stromal tumor

Inhibitor resistance mutants have also been identified in tumors from patients with gastrointestinal stromal tumors (GISTs).38 These tumors are driven by activating mutations of KIT and PDGFRa receptor tyrosine kinases.39 Both imatinib and sunitinib are indicated to treat surgically inoperable GISTs. However, complete responses are rare and many patients go on to develop secondary resistance.40... 

Imatinib is a protein-tyrosine-kinase inhibitor. Imatinib inhibits proliferation and induces apoptosis in BCR-ABL positive cell lines as well as fresh leukemic cells from Philadelphia chromosome-positive (Ph-r) chronic myeloid leukemia (CML). Imatinib inhibits tumor growth of BCR-ABL transfected murine myeloid cells and BCR-ABL positive leukemia lines derived from CML patients in blast crisis. It also inhibits the receptor tyrosine kinases for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, and inhibits PDGF- and SCF-mediated cellular events. It is indicated in the treatment of newly diagnosed adult patients with Ph-t CML in chronic phase patients with Ph-t CML in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha treatment children with Ph-t chronic phase CML whose disease has recurred after stem cell transplant or who are resistant to interferon-alpha therapy and treatment of gastrointestinal stromal tumors (GIST). 

A. Gronchi, R. Bertulli, M. Colecchia, P.G. Casali, M.A. Pierotti, S. Pilotti, A new mutation in the kit atp pocket causes acquired resistance to imatinib in a gastrointestinal stromal tumor patient, Gastroenterology 2004, 127(1). 294-9. 

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. 

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