GEIS guidelines for gastrointestinal sarcomas (GIST)

Poveda, Andrés; Muro, Xavier García del; Löpez‐Guerrero, José Antonio; Cubedo, Ricardo; Martínez, Virginia; Romero, Ignacio; Serrano, César; Valverde, Claudia; Martin‐Broto, Javier

doi:10.1016/j.ctrv.2016.11.011

Cited by 118 publications

(136 citation statements)

References 110 publications

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“…KIT can be targeted by small‐molecule inhibitors, such as imatinib, which are approved for the treatment of gastrointestinal sarcomas with mutations in exon 11, encompassing the juxtamembrane region with amino acids 550 through 591 . Melanoma patients with mutated KIT also might benefit from imatinib, but this was not confirmed for patients with amplified KIT .…”

Section: Resultsmentioning

confidence: 99%

The identification of patient‐specific mutations reveals dual pathway activation in most patients with melanoma and activated receptor tyrosine kinases in BRAF/NRAS wild‐type melanomas

Appenzeller

Gesierich

Thiem

et al. 2018

Cancer

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Background Increasing knowledge of cancer genomes has triggered the development of specific targeted inhibitors, thus providing a valuable therapeutic pool. Methods In this report, the authors analyze the presence of targetable alterations in 136 tumor samples from 92 patients with melanoma using a comprehensive approach based on targeted DNA sequencing and supported by RNA and protein analysis. Three topics of high clinical relevance are addressed: the identification of rare, activating alterations; the detection of patient‐specific, co‐occurring single nucleotide variants (SNVs) and copy number variations (CNVs) in parallel pathways; and the presence of cancer‐relevant germline mutations. Results The analysis of patient‐matched blood and tumor samples was done with a custom‐designed gene panel that was enriched for genes from clinically targetable pathways. To detect alterations with high therapeutic relevance for patients with unknown driver mutations, genes that are untypical for melanoma also were included. Among all patients, CNVs were identified in one‐third of samples and contained amplifications of druggable kinases, such as CDK4, ERBB2, and KIT. Considering SNVs and CNVs, 60% of patients with metastases exhibited co‐occurring activations of at least 2 pathways, thus providing a rationale for individualized combination therapies. Unexpectedly, 9% of patients carry potentially protumorigenic germline mutations frequently affecting receptor tyrosine kinases. Remarkably two‐thirds of BRAF/NRAS wild‐type melanomas harbor activating mutations or CNVs in receptor tyrosine kinases. Conclusions The results indicate that the integrated analysis of SNVs, CNVs, and germline mutations reveals new druggable targets for combination tumor therapy.

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Section: Resultsmentioning

confidence: 99%

The identification of patient‐specific mutations reveals dual pathway activation in most patients with melanoma and activated receptor tyrosine kinases in BRAF/NRAS wild‐type melanomas

Appenzeller

Gesierich

Thiem

et al. 2018

Cancer

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“…Although GISTs can be successfully treated with imatinib mesylate or other TKIs, new therapeutic options are needed because complete responses are rare and most patients develop resistance to these drugs over time (Poveda et al, 2017). Based on our previous finding that the adaptor SH3BP2 was able to regulate KIT and MITF expression and viability on mast cells (Ainsua-Enrich et al, 2015), we explored the ability of this protein to regulate these events in GIST.…”

Section: Discussionmentioning

confidence: 99%

Silencing of adaptor protein SH3BP2 reduces KIT/PDGFRA receptors expression and impairs gastrointestinal stromal tumors growth

et al. 2018

Self Cite

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Gastrointestinal stromal tumors (GISTs) represent about 80% of the mesenchymal neoplasms of the gastrointestinal tract. Most GISTs contain oncogenic KIT (85%) or PDGFRA (5%) receptors. The kinase inhibitor imatinib mesylate is the preferential treatment for these tumors; however, the development of drug resistance has highlighted the need for novel therapeutic strategies. Recently, we reported that the adaptor molecule SH3 Binding Protein 2 (SH3BP2) regulates KIT expression and signaling in human mast cells. Our current study shows that SH3BP2 is expressed in primary tumors and cell lines from GIST patients and that SH3BP2 silencing leads to a downregulation of oncogenic KIT and PDGFRA expression and an increase in apoptosis in imatinib‐sensitive and imatinib‐resistant GIST cells. The microphthalmia‐associated transcription factor (MITF), involved in KIT expression in mast cells and melanocytes, is expressed in GISTs. Interestingly, MITF is reduced after SH3BP2 silencing. Importantly, reconstitution of both SH3BP2 and MITF restores cell viability. Furthermore, SH3BP2 silencing significantly reduces cell migration and tumor growth of imatinib‐sensitive and imatinib‐resistant cells in vivo. Altogether, SH3BP2 regulates KIT and PDGFRA expression and cell viability, indicating a role as a potential target in imatinib‐sensitive and imatinib‐resistant GISTs.

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“…Several studies suggest that kit-negative GISTs show clinical, pathological and genetic differences form Kit-positive GISTs [15]. Neither CT nor MRI are currently able to differentiate between conventional GISTs and atypical (c-kit negative) GISTs [16].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Extragastrointestinal stromal tumor of lesser omentum: a challenging radiological and histological diagnosis

et al. 2015

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GEIS guidelines for gastrointestinal sarcomas (GIST)

Cited by 118 publications

References 110 publications

The identification of patient‐specific mutations reveals dual pathway activation in most patients with melanoma and activated receptor tyrosine kinases in BRAF/NRAS wild‐type melanomas

The identification of patient‐specific mutations reveals dual pathway activation in most patients with melanoma and activated receptor tyrosine kinases in BRAF/NRAS wild‐type melanomas

Silencing of adaptor protein SH3BP2 reduces KIT/PDGFRA receptors expression and impairs gastrointestinal stromal tumors growth

Extragastrointestinal stromal tumor of lesser omentum: a challenging radiological and histological diagnosis

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