Biology of Gastrointestinal Stromal Tumors:KITMutations and Beyond

Abstract

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the digestive tract. Aspects of the morphology and immunophenotype in GISTs resemble those in the interstitial cells of Cajal (ICC), which are a specialized cell type responsible for coordinating peristaltic activity throughout the gastrointestinal tract. Therefore, it is possible that GISTs result from transformation of nonneoplastic progenitor cells that would normally differentiate towards an ICC endpoint. Activation of the KIT receptor tyrosine kinase is required for differentiation and proliferation of nonneoplastic ICC, and oncogenic KIT mutations are a crucial event in the development of most GISTs. These mutations can involve either the extracellular or intracellular domains of the KIT receptor, giving rise to conformational changes that enable constitutive, ligand-independent, activation of the KIT protein. Oncogenic KIT activation leads to phosphorylation of various substrate proteins and, in turn, to activation of signal transduction cascades regulating cell proliferation, apoptosis, chemotaxis, and adhesion. Recently, a small molecule tyrosine kinase inhibitor (STI571, imatinib mesylate, Gleevec) directed against the enzymatic (kinase) domain of the KIT protein was found to produce dramatic clinical responses as monotherapy for metastatic GISTs. This review focuses on the biological and molecular genetic principles of GISTs, and particularly the role of mutant KIT as a therapeutic target.

Silent mutations in KIT and PDGFRA and coexpression of receptors with SCF and PDGFA in Merkel cell carcinoma: implications for tyrosine kinase-based tumorigenesis

“…27 None of the regions analyzed contained any deletions or insertions. However, we identified what appear to be either mutations or polymorphisms in exon 17 of KIT and in exons 10, 12 and 18 of PDGFRA (Table 3).…”

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

“…c-KIT, a member of the type III receptor tyrosine kinase family, is important for hematopoiesis, melanogenesis, and gametogenesis as well as the development of the interstitial cells of Cajal, which are believed to be the nonmalignant precursor cells of GIST (16). Upon ligand binding, c-KIT dimerizes, undergoes autophosphorylation, and activates a variety of downstream signaling pathways and molecules, including MAPK, PI3K-AKT, Src, and JAK/STAT (17).…”

Activation mutations of human c-KIT resistant to imatinib mesylate are sensitive to the tyrosine kinase inhibitor PKC412

“…Mutations of c-KIT have been associated with hematopoietic and nonhematopoietic tumors, including systemic mast cell disease (SMCD), [2][3][4] acute myeloid leukemia (AML), [5][6][7][8] and gastrointestinal stromal tumors (GISTs). [9][10][11][12] The tyrosine kinase inhibitor imatinib mesylate (Gleevec; Novartis Pharma AG, Basel, Switzerland) is efficacious in the majority of patients with GIST harboring c-KIT mutations. 9,13 c-KIT is most commonly activated in GIST tumors by small deletions in the JM that are thought to constitutively activate the tyrosine kinase by loss of autoinhibitory function.…”

“…[9][10][11][12] The tyrosine kinase inhibitor imatinib mesylate (Gleevec; Novartis Pharma AG, Basel, Switzerland) is efficacious in the majority of patients with GIST harboring c-KIT mutations. 9,13 c-KIT is most commonly activated in GIST tumors by small deletions in the JM that are thought to constitutively activate the tyrosine kinase by loss of autoinhibitory function. 14 All c-KIT JM deletion mutants tested thus far are sensitive to inhibition by imatinib mesylate.…”