Role for the Proapoptotic Factor BIM in Mediating Imatinib-induced Apoptosis in a c-KIT-dependent Gastrointestinal Stromal Tumor Cell Line

Abstract

The c-KIT receptor tyrosine kinase is constitutively activated and oncogenic in the majority of gastrointestinal stromal tumors. The identification of selective inhibitors of c-KIT, such as imatinib, has provided a novel therapeutic approach in the treatment of this chemotherapy refractory tumor. However, despite the clinical importance of these findings and the potential it provides as a model system for understanding targeted therapy, this approach has not yielded curative outcomes in most patients, and the biochemical pathways connecting c-KIT inhibition to cell death are not completely understood. Here, we show that inhibition of c-KIT with imatinib in gastrointestinal stromal tumors (GISTs) triggered the up-regulation of the proapoptotic protein BIM via both transcriptional and post-translational mechanisms. The inhibition of c-KIT by imatinib increased levels of the dephosphorylated and deubiquitinated form of BIM as well as triggered the accumulation of the transcription factor FOXO3a on the BIM promoter to activate transcription of BIM mRNA. Furthermore, using RNA interference directed against BIM, we demonstrated that BIM knockdown attenuated the effects of imatinib, suggesting that BIM functionally contributes to imatinib-induced apoptosis in GIST. The identification and characterization of the pathways that mediate imatinib-induced cell death in GIST provide for a better understanding of targeted therapy and may facilitate the development of new therapeutic approaches to further exploit these pathways.Therapies that selectively target essential molecular pathways of cancer cells possess the potential to increase the effectiveness of therapy while decreasing the side effects associated with traditional cytotoxic chemotherapy. One example that has evoked considerable interest in both the laboratory and clinic is the identification in GI stromal tumors of activating mutations in the c-KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) receptor tyrosine kinase gene coupled with the development of targeted c-KIT inhibitors such as imatinib (1). Gastrointestinal stromal tumors (GISTs) 2 are the most common mesenchymal tumor of the gastrointestinal tract, and ϳ80% of GISTs harbor activating c-KIT mutations (2). While surgical resection of localized disease can be curative, GISTs are poorly responsive to cytotoxic chemotherapy, and for metastatic disease, there were few therapeutic options prior to the advent of targeted c-KIT therapies (2). However, although ϳ80% of patients with metastatic GIST respond to imatinib therapy, responses are rarely complete, and patients eventually progress on therapy, often due to the development of secondary, imatinib-resistant c-KIT mutations (3).Evidence suggests that activated c-KIT drives GIST cell survival through multiple pathways and that the specific c-KIT mutation type may influence the degree of activation of the different downstream signal transduction pathways (4). Accordingly, the key downstream mediators of imatinib-induced cell death in GISTs ...

A common BIM deletion polymorphism mediates intrinsic resistance and inferior responses to tyrosine kinase inhibitors in cancer

“…Our data also highlight how a single germline polymorphism can strongly affect clinical outcomes in different cancers that share a common biology and probably reflect the central role of BIM in mediating TKI sensitivity in these diseases 8,11,13 . We anticipate that the list of cancers in which the BIM polymorphism influences TKI responses will expand to include others that also depend on BIM expression for TKI sensitivity [38][39][40] .…”

Imatinib mesylate induction of ROS-dependent apoptosis in melanoma B16F0 cells

“…Gordon and Fisher reported STI571-induced apoptosis in GIST cells through upregulation of proapoptotic BIM protein expression [23]. Biswas et al indicated that STI571 induced apoptosis in retinal ganglion RGC-5 cells through inhibiting PDGF-induced PI3K/Akt survival signaling [24].…”

Phosphoinositide 3-Kinase Inhibitors Combined with Imatinib in Patient-Derived Xenograft Models of Gastrointestinal Stromal Tumors: Rationale and Efficacy

“…Despite the secondary KIT exon17 mutation, in our experiments GIST48 showed a strong response to imatinib in terms of reduction of tumor burden and mitotic activity. Moderate to strong responses to imatinib have been previously described in GIST48, both in vitro and in vivo, and might be due to the heterozygous nature of the secondary KIT exon17 mutation in GIST48 (14,15,23,32). Because of the lack of imatinib resistance in the GIST48 model, we decided not to further test PI3Kis in this model.…”