Gain-of-function mutations of platelet-derived growth factor receptor α gene in gastrointestinal stromal tumors

Hirota, Seiichi; Ohashi, Akiko; Nishida, Toshirou; Isozaki, Koji; Kinoshita, Kazuo; Shinomura, Yasuhisa; Kitamura, Yukihiko

doi:10.1016/s0016-5085(03)01046-1

Cited by 604 publications

(450 citation statements)

References 19 publications

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“…When expressed in transfected cell lines, mutant forms of PDGFRA have constitutive kinase activity in the absence of their ligand, PDGF-A, 37,38 the activated downstream pathways are identical to those in KIT-mutant GISTs, 37,39 and PDGFRA is also stabilized by HSP90. 40 In addition, both types of tumors are immunopositive Figure 3 (a) KIT and PDGFRA cell signaling pathways.…”

Section: Platelet-derived Growth Factor Receptor-amentioning

confidence: 99%

“…112 On the basis of in vitro data, the most common PDGFRA mutation in GISTs, D842V, is fully resistant to the effects of imatinib. 34,38,127,128 This mutation favors the active conformation of the kinase domain and consequently disfavors imatinib binding. 34,129,130 This is corroborated by clinical results, as patients with PDGFRA D842V-mutant GIST have low response rates and very short progression-free and overall survivals during imatinib treatment.…”

Section: Primary Resistancementioning

confidence: 99%

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Gastrointestinal stromal tumors: what do we know now?

2014

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Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the GI tract, arising from the interstitial cells of Cajal, primarily in the stomach and small intestine. They manifest a wide range of morphologies, from spindle cell to epithelioid, but are immunopositive for KIT (CD117) and/or DOG1 in essentially all cases. Although most tumors are localized at presentation, up to half will recur in the abdomen or spread to the liver. The growth of most GISTs is driven by oncogenic mutations in either of two receptor tyrosine kinases: KIT (75% of cases) or PDGFRA (10%). Treatment with tyrosine kinase inhibitors (TKIs) such as imatinib, sunitinib, and regorafenib is effective in controlling unresectable disease; however, drug resistance caused by secondary KIT or PDGFRA mutations eventually develops in 90% of cases. Adjuvant therapy with imatinib is commonly used to reduce the likelihood of disease recurrence after primary surgery, and for this reason assessing the prognosis of newly resected tumors is one of the most important roles for pathologists. Approximately 15% of GISTs are negative for mutations in KIT and PDGFRA. Recent studies of these so-called wild-type GISTs have uncovered a number of other oncogenic drivers, including mutations in neurofibromatosis type I, RAS genes, BRAF, and subunits of the succinate dehydrogenase complex. Routine genotyping is strongly recommended for optimal management of GISTs, as the type and dose of TKI used for treatment is dependent on the mutation identified.

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Section: Platelet-derived Growth Factor Receptor-amentioning

confidence: 99%

Section: Primary Resistancementioning

confidence: 99%

Gastrointestinal stromal tumors: what do we know now?

2014

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“…Most GISTs (85%) contain gain-offunction KIT oncogenic mutations, which are associated with constitutive KIT tyrosine phosphorylation, and activation of cell proliferation and survival signaling pathways (Duensing et al, 2004b). Alternately, a small subset of GISTs has oncogenic mutations in the gene encoding platelet-derived growth factor receptor alpha (PDGFRA) that confer constitutive activation (Heinrich et al, 2003;Hirota et al, 2003). Although KIT and PDGFRA oncogenic mutations are mutually exclusive in GISTs, approximately 30% of KIT-mutant GISTs express PDGFRA strongly (Heinrich et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…KIT undergoes homodimerization and autophosphorylation when bound by the ligand, stem cell factor, or when activated by oncogenic mutations (Hirota et al, 1998;Rubin et al, 2001). In addition, KIT can heterodimerize with the PDGFR family members FLT3 (Otto et al, 2001) and PDGFRA (Hirota et al, 2003), and presumably with other RTKs. Therefore, the clinical success of KIT inhibitors in patients with GIST might result from inactivation of KIT downstream signaling pathways and KIT heterodimerization partners.…”

Section: Introductionmentioning

confidence: 99%

KIT oncoprotein interactions in gastrointestinal stromal tumors: therapeutic relevance

Zhu

Fletcher

et al. 2007

Oncogene

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Most gastrointestinal stromal tumors (GISTs) express oncogenic and constitutively active forms of the KIT or platelet-derived growth factor receptor alpha (PDGFRA) receptor tyrosine kinase proteins, and these kinase oncoproteins serve as targets for effective therapies. Given that mutant KIT oncoproteins serve crucial transforming roles in GISTs, we evaluated interactions with the KIT oncoproteins and determined signaling pathways that are dependent on KIT oncogenic activation in GISTs. Tyrosine-phosphorylated KIT oncoproteins interacted with PDGFRA, PDGFRB, phosphatidylinositol 3-kinase (PI3-K) and PKCh in GIST cells, and these interactions were abolished by KIT inhibition with imatinib or PKC412 or KIT RNAi. Notably, tyrosine-phosphorylated PDGFRA was prominent in frozen GIST tumors expressing KIT oncoproteins, suggesting that KIT-mediated PDGFRA phosphorylation is an efficient and biologically consequential mechanism in GISTs. Activated signaling intermediates were identified by immunoaffinity purification of tyrosine-phosphorylated proteins in GIST cells before and after treatment with KIT inhibitors, and these analyses show that GRB2, SHC, CBL and MAPK activation are largely KIT dependent in GISTs, whereas PI3-K, STAT1 and STAT3 activation are partially KIT dependent. In addition, we found that phosphorylation of several tyrosine kinase proteins -including JAK1 and EPHA4 -did not depend on KIT activation. Likewise, paxillin activation was independent of the KIT oncogenic signal. These studies identify signaling pathways that can provide both KIT-dependent and KIT-independent therapeutic synergies in GIST, and thereby highlight clinical strategies that might consolidate GIST therapeutic response to KIT/PDGFRA inhibition.

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“…Recent progress in the understanding of the molecular mechanisms of their oncogenesis has contributed to the improvements in their diagnosis and treatment. 1,2 The discovery that almost all GISTs express KIT/CD117 antigen has led to the development of imatinib mesylate (imatinib, Glivec; Novartis, Basel, Switzerland) for the targeted therapy of GISTs. 3 Several clinical trials have shown the effectiveness of imatinib in the treatment of advanced, metastatic and recurrent GISTs.…”

mentioning

confidence: 99%

Stage and histological grade of gastrointestinal stromal tumors based on a new approach are strongly associated with clinical behaviors

Hou

Zhou

et al. 2009

Modern Pathology

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Tumor stage and grade for gastrointestinal stromal tumors are poorly defined. To develop a better evaluation system, we assessed 12 clinical and pathological parameters in 613 patients with follow-up information. These parameters were classified into two gross spread parameters including liver metastasis and peritoneal dissemination, five microscopic spread parameters including lymph node metastasis, vascular, fat, nerve and mucosal infiltration, and five histological parameters including mitotic count Z10 per 50 high-power fields, muscularis propria infiltration, coagulative necrosis, perivascular pattern and severe nuclear atypia. The 5-year disease-free survival and overall survival of 293 patients without any of these predictive parameters of malignancy were 99% and 100%, respectively. They were regarded as nonmalignant and further evaluations on the stage and grade of these tumors were not performed. At least one and at most seven predictive parameters of malignancy were identified in 320 patients. For these patients, the 5-year disease-free survival and overall survival rates were 44% (mean 6.7 years) and 60% (mean 9.3 years), respectively. The disease-free survival showed significant difference between patients with and without gross spread (Po0.0001), with and without microscopic spread (P ¼ 0.0009). Disease-free survival and overall survival were associated with the number of predictive parameters of malignancy in patients without gross spread (Po0.0001 for both disease-free survival and overall survival), but not in patients with gross spread (P ¼ 0.882 and 0.441, respectively). Malignant gastrointestinal stromal tumors could be divided into clinical stage I and II based on the absence and presence of gross spread, respectively. The degree of malignancy of patients in clinical stage I could be graded according to the number of predictive parameters of malignancy. Patients in clinical stage II were of the highest degree of malignancy regardless of the number of parameters. We found that the clinical stage and grade were strongly associated with prognosis.

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Gain-of-function mutations of platelet-derived growth factor receptor α gene in gastrointestinal stromal tumors

Cited by 604 publications

References 19 publications

Gastrointestinal stromal tumors: what do we know now?

Gastrointestinal stromal tumors: what do we know now?

KIT oncoprotein interactions in gastrointestinal stromal tumors: therapeutic relevance

Stage and histological grade of gastrointestinal stromal tumors based on a new approach are strongly associated with clinical behaviors

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