STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications

Mutations in the c-KIT receptor occur somatically in many sporadic Gastroin testinal Stromal Tumors (GIST), and similar mutations have been identified at the germline level in kindreds with multiple GISTs. These mutations acti vate the tyrosine kinase activity of e-KIT and induce constitutive signalin g. To investigate the function of activated c-KIT in GIST, we established a human GIST cell line, GIST882, which expresses an activating KIT mutation (K642E) in the first part of the cytoplasmic split tyrosine kinase domain. Notably, the K642E substitution is encoded by a homozygous exon 13 missense mutation, and, therefore, GIST882 cells do not express native KIT. GIST882 c-KIT protein is constitutively tyrosine phosphorylated, but tyrosine phos phorylation was rapidly and completely abolished after incubating the cells with the selective tyrosine kinase inhibitor STI571. Furthermore, GIST882 cells evidenced decreased proliferation and the onset of apoptotic cell dea th after prolonged incubation with STI571. Similar results were obtained af ter administering STI571 to a primary GIST cell culture that expressed a c- KIT exon I I juxtamembrane mutation (K558NP). These cell-culture-based stud ies support an important role for c-KIT signaling in GIST and suggest thera peutic potential for STI571 in patients afflicted by this chemoresistant tu mor.