Abstract
L576P is a rare KIT mutation often reported in cancers other than gastrointestinal stromal tumors (GIST). In GISTs, it correlates with features linked to an aggressive phenotype, eventually resulting in secondary mutations. In vitro findings point out that L576P/KIT is constitutively activated,and shows poor imatinib sensitivity. In this work, histological,i mmunohistochemical,a nd biochemical analyses, coupled with mutational-molecular analysis and fluorescence in situ hybridization, were applied to surgical specimens. In parallel, the affinities of wild-type, L576P/KIT, and Δ559/KIT for imatinib were estimated by in silico studies. Despite imatinib treatment and the apparent clinical-imaging response, the detected histological response was very low. KIT resulted, expressed and activated in absence of secondary mutations, BRAF/NRAS mutations, an d KIT/PDGFRA gene alterations. Computer modeling proved that L576P/KIT is two times less sensitive than the wild-type counterpart and considerably less affine to imatinib than the sensitive Δ559/KIT. Accordingly, the modeling evidence strongly supports the lack of tumoral regression we observed at the histological level.
| Original language | English |
|---|---|
| Pages (from-to) | 2491-2495 |
| Number of pages | 5 |
| Journal | Molecular Cancer Therapeutics |
| Volume | 8 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - Sep 1 2009 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
Activate and resist : L576P-KIT in GIST. / Conca, Elena; Negri, Tiziana; Gronchi, Alessandro; Fumagalli, Elena; Tamborini, Elena; Pavan, Giovanni Maria; Fermeglia, Maurizio; Pierotti, Marco A.; Pricl, Sabrina; Pilotti, Silvana.
In: Molecular Cancer Therapeutics, Vol. 8, No. 9, 01.09.2009, p. 2491-2495.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Activate and resist
T2 - L576P-KIT in GIST
AU - Conca, Elena
AU - Negri, Tiziana
AU - Gronchi, Alessandro
AU - Fumagalli, Elena
AU - Tamborini, Elena
AU - Pavan, Giovanni Maria
AU - Fermeglia, Maurizio
AU - Pierotti, Marco A.
AU - Pricl, Sabrina
AU - Pilotti, Silvana
PY - 2009/9/1
Y1 - 2009/9/1
N2 - L576P is a rare KIT mutation often reported in cancers other than gastrointestinal stromal tumors (GIST). In GISTs, it correlates with features linked to an aggressive phenotype, eventually resulting in secondary mutations. In vitro findings point out that L576P/KIT is constitutively activated,and shows poor imatinib sensitivity. In this work, histological,i mmunohistochemical,a nd biochemical analyses, coupled with mutational-molecular analysis and fluorescence in situ hybridization, were applied to surgical specimens. In parallel, the affinities of wild-type, L576P/KIT, and Δ559/KIT for imatinib were estimated by in silico studies. Despite imatinib treatment and the apparent clinical-imaging response, the detected histological response was very low. KIT resulted, expressed and activated in absence of secondary mutations, BRAF/NRAS mutations, an d KIT/PDGFRA gene alterations. Computer modeling proved that L576P/KIT is two times less sensitive than the wild-type counterpart and considerably less affine to imatinib than the sensitive Δ559/KIT. Accordingly, the modeling evidence strongly supports the lack of tumoral regression we observed at the histological level.
AB - L576P is a rare KIT mutation often reported in cancers other than gastrointestinal stromal tumors (GIST). In GISTs, it correlates with features linked to an aggressive phenotype, eventually resulting in secondary mutations. In vitro findings point out that L576P/KIT is constitutively activated,and shows poor imatinib sensitivity. In this work, histological,i mmunohistochemical,a nd biochemical analyses, coupled with mutational-molecular analysis and fluorescence in situ hybridization, were applied to surgical specimens. In parallel, the affinities of wild-type, L576P/KIT, and Δ559/KIT for imatinib were estimated by in silico studies. Despite imatinib treatment and the apparent clinical-imaging response, the detected histological response was very low. KIT resulted, expressed and activated in absence of secondary mutations, BRAF/NRAS mutations, an d KIT/PDGFRA gene alterations. Computer modeling proved that L576P/KIT is two times less sensitive than the wild-type counterpart and considerably less affine to imatinib than the sensitive Δ559/KIT. Accordingly, the modeling evidence strongly supports the lack of tumoral regression we observed at the histological level.
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UR - http://www.scopus.com/inward/citedby.url?scp=70349487536&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-09-0662
DO - 10.1158/1535-7163.MCT-09-0662
M3 - Article
C2 - 19723893
AN - SCOPUS:70349487536
VL - 8
SP - 2491
EP - 2495
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 9
ER -