KIT hyperactivation in imatinib-resistant GIST: Implications for salvage therapies

9034 Background: Many GIST pts respond to KIT inhibition with imatinib (IM), yet eventually develop resistance. IM resistance mechanisms are heterogeneous, and little is known about KIT functional roles in IM-resistant GIST. Methods: GIST cell lines were established from biopsy specimens. Biological consequences of KIT, PI3-K, PLCgamma, MEK/MAPK and mTOR inhibition were determined by immunoblotting for protein activation, and by cell proliferation and apoptosis assays. Results: Novel cell lines, GIST430 and GIST48, were developed from GISTs progressing clinically on IM. These lines contain primary IM-sensitive KIT juxtamembrane mutations and secondary IM-resistance mutations in the ATP-binding (GIST430) and catalytic (GIST48) portions of the KIT kinase domain. Kinase activation was compared with GIST882 cells, which contain only a primary IM-sensitive mutation. KIT expression was equally strong in the 3 GIST cell lines, whereas KIT activation was 3-to-6 fold higher in GIST430 and GIST48 than in GIST882. I...