Targeted therapies in gastrointestinal stromal tumors Journal Article
| Author: | Antonescu, C. R. |
| Article Title: | Targeted therapies in gastrointestinal stromal tumors |
| Abstract: | The discovery of constitutive KIT activation as the central mechanism of gastrointestinal stromal tumor (GIST) pathogenesis suggested that inhibiting or blocking KIT signaling might be the milestone in the targeted therapy of GISTs. Indeed, imatinib mesylate inhibits KIT kinase activity and represents the front-line drug for the treatment of unresectable and metastatic GISTs. Despite a high rate of response in patients with KIT exon 11 mutated GISTs, the failure rate is significantly higher in patients with a wild-type genotype, suggesting an alternative activated pathway not targeted by imatinib therapy. The most common mechanism of resistance is through polyclonal acquisition of second-site mutations in the kinase domain, which highlights the future therapeutic challenges in salvaging these patients after failing kinase inhibitors monotherapies. This review article summarizes the recent knowledge accumulated on targeted therapy in GIST, based on the central role of KIT oncogenic activation and subsequent signal transduction in the pathogenesis of GIST. In addition, we provide an updated discussion on diagnostic pitfalls, including changes secondary to imatinib response and resistance. © 2008 Elsevier Inc. All rights reserved. |
| Keywords: | signal transduction; cancer chemotherapy; cancer survival; treatment response; unclassified drug; gene mutation; exon; mutation; clinical trial; pathogenesis; sorafenib; sunitinib; drug withdrawal; monotherapy; antineoplastic agents; drug targeting; cancer patient; animals; gastrointestinal stromal tumor; imatinib; platelet derived growth factor alpha receptor; stem cell factor; drug inhibition; gastrointestinal stromal tumors; proto-oncogene proteins c-kit; metastasis; mitogen activated protein kinase inhibitor; antineoplastic activity; cytotoxicity; drug structure; drug resistance; dasatinib; structure activity relation; phosphatidylinositol 3 kinase; cell heterogeneity; protein tyrosine kinase inhibitor; drug dose escalation; drug delivery systems; oncogene; survival time; gene activation; transcription regulation; drug response; heat shock protein 90 inhibitor; tanespimycin; heat shock protein 90; targeted therapy; flavopiridol; alternative medicine; gist; nilotinib; drug substitution; antiangiogenic activity; b raf kinase; genetic heterogeneity; protein kinase c inhibitor; molecular therapy; midostaurin; kinase inhibitors; mitogen activated protein kinase kinase inhibitor |
| Journal Title: | Seminars in Diagnostic Pathology |
| Volume: | 25 |
| Issue: | 4 |
| ISSN: | 0740-2570 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2008-11-01 |
| Start Page: | 295 |
| End Page: | 303 |
| Language: | English |
| DOI: | 10.1053/j.semdp.2008.08.004 |
| PUBMED: | 19013895 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 12" - "Export Date: 17 November 2011" - "CODEN: SDPAE" - "Source: Scopus" |
