The insulin-like growth factor system as a potential therapeutic target in gastrointestinal stromal tumors.
The majority of gastrointestinal stromal tumors (GISTs) are characterized by oncogenic gain-of-function mutations in the receptor tyrosine kinase (RTK) c-KIT with a minority in PDGFRalpha. Therapy for GISTs has been revolutionized by the use of the selective tyrosine kinase inhibitor imatinib mesylate (IM). For the subset (approximately 10-15%) of GISTs that lack oncogenic mutations in these receptors, the genetic changes driving tumorigenesis are unknown. We recently reported that the gene encoding the insulin-like growth factor 1 receptor (IGF-1R) is amplified in a subset of GISTs, and the IGF-1R protein is overexpressed in wild-type and pediatric GISTs. In this report we present a more complete picture of the involvement of components of the insulin-like growth factor-signaling pathway in the pathogenesis of GISTs. We also discuss how the IGF pathway may provide additional molecular targets for the treatment of GISTs that respond poorly to IM therapy.
Belinsky
Martin G
MG
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.
Rink
Lori
L
Cai
Kathy Q
KQ
Ochs
Michael F
MF
Eisenberg
Burton
B
Huang
Min
M
von Mehren
Margaret
M
Godwin
Andrew K
AK
D001549:Benzamides; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction; D013002:Somatomedins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000627:therapeutic use
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D013002:Somatomedins; D000068877:Imatinib Mesylate; D051096:Proto-Oncogene Proteins c-ret