STI571 in GIST
Deregulation of c-Kit has been implicated in the etiology of a number of cancers, including AML, small cell lung cancers, gliomas, testicular cancer, and GIST. The majority of the GIST patients carry mutations in c-Kit that result in constitutively enhanced ligand-independent PTK activity, which appears to play a key role in the pathogenesis of these tumors (Hirota et al. 1998; Lux et al. 2000; Demetri et al. 2002; Heinrich et al. 2002; Joensuu et al. 2002). Since these Kit mutations lead to uncontrolled cell proliferation via permanent stimulation of downstream signaling pathways, it was thought that GIST should prove sensitive to STI571. Although the activity of STI571 against c-Kit was initially of concern, due to the important role that this receptor appears to play in hematopoiesis, the c-Kit-activating mutations associated with GIST supported the use of STI571 in the treatment of this tumor, which is refractory to chemotherapy and radiation. The remarkable clinical activity of STI571 led to its approval in February 2002 for the treatment of advanced GISTs.
Clinical responses in GIST patients following treatment with STI571 appear to be closely associated with the presence of activating c-Kit mutations, as patients expressing wild-type Kit had a significantly lower response (Heinrich et al. 2003a,b). In the subset of patients that expressed wild-type c-Kit and responded to STI571 treatment, activating mutations in the PDGFRa have been found. These clinical trials demonstrated for the first time the presence of naturally occurring mutated forms of PDGFRa. The mutational status of PDGFRa could explain response and sensitivity to ima-tinib in GISTs lacking c-Kit mutations, because mutations in c-Kit and in PDGFRa appear to be mutually exclusive.
Although STI571 is an effective therapy in GIST with an impressive response rate of 62% after 15 months of treatment (Demetri et al. 2002; Joensuu et al. 2002), relapses have been observed in up to 20% of patients. It seems very likely that one of the underlying mechanisms for this STI571 re sistance will be the emergence of clones carrying point-mutations in the kinase domain of c-Kit, in close analogy to the resistance induced in Bcr-Abl by STI571 in CML.
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