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• W3000207856 abstract "ABSTRACT Background In GIST, KIT/PDGFRA mutations correlate with response to TKI. The exon 18 PDGFRA-D842V mutation is known to be resistant to imatinib and sunitinib. Activation of PDGFRA involves two main signal transduction pathways, RAS/MEK/ERK, which involves BRAF, and PI3K-AKT. We used sorafenib in three pts with a PDGFRA-D842V mutated metastatic GIST. Methods Since January 2010, 3 PDGFRA-D842V mutated GIST pts (age: 57, 71, 72 yrs) have been treated with sorafenib 400 mg twice daily, on an individual use basis. Two pts were progressing on imatinib in association to mTOR inhibitors (sirolimus and everolimus), while the third had four previous lines of therapy. Molecular/biochemical analyses were performed on cryopreserved material taken before sorafenib treatment in two of the three patients (one biopsy and one surgical specimen). A primary cell culture was obtained from one patient. Results One pt had a Choi's response 3 mos after starting the treatment; the others a RECIST response at 2 mos. The first pt had a tumor progression after 12 mos from starting therapy and 9 mos from tumor response. The second pt had a partial response lasting 15 mos. Treatment was relatively well tolerated, with G3 skin toxicity in one pt, causing a dose reduction. Biochemical analyses on pretreatment tumors revealed activated S6K and S6, both downstream mTOR, as well as ERK1/2 strong activation. The primary cell culture was treated with sorafenib 0.5 and 1 µM and phosphorylation switch-off of both S6K and S6 (Ser 240/244), associated with a retained ERK1/2 expression/activation, was observed. Further analyses are ongoing to verify which pathways converging on mTOR are inhibited by sorafenib. Conclusions In the unresponsive PDGFRA-D842V mutated GIST we saw clinical signs of antitumor activity of sorafenib in 3 pts. This was consistent with biochemical analyses, which showed an inhibitory effect downstream mTOR. This clinical setting constitutes a high-priority unmet medical need, since very few clinical data are known and no functional analyses on sorafenib activity have been reported so far. Disclosure P.G. Casali: Advisory role and honoraria for lectures: Novartis Pharma, Pfizer. Advisory role: Bayer. All other authors have declared no conflicts of interest." @default.
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• W3000207856 date "2012-09-01" @default.
• W3000207856 modified "2023-09-29" @default.
• W3000207856 title "Response to Sorafenib in PDGFRA-D842V Mutated Metastatic Gastrointestinal Stromal Tumor (GIST), Supported by Biomolecular Functional Analyses" @default.
• W3000207856 doi "https://doi.org/10.1016/s0923-7534(20)34036-9" @default.
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