期刊
CLINICAL CANCER RESEARCH
卷 14, 期 15, 页码 4908-4914出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-07-1772
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资金
- NCI NIH HHS [P50 CA097007, 1P50 CA97007, 5P30 CA16672, CA16672, P30 CA016672] Funding Source: Medline
- NIDCR NIH HHS [R01 DE013954, R01 DE-13954, R01 DE013954-05] Funding Source: Medline
Purpose: Papillary thyroid carcinomas (PTC) are the most common type of thyroid malignancy with one of the two mutations, RET/PTC rearrangement or BRAF mutation. Both mutations are able to activate the MEK/ERK signaling transduction pathway and result in the activation of transcription factors that regulate cellular proliferation, differentiation, and apoptosis. Sorafenib (Nexavar, BAY 43-9006) is a multikinase inhibitor, and in this study, we tested its effects on PTC cells carrying either mutation. Experimental Design: The effects of sorafenib on cell proliferation and signaling were evaluated in vitro on PTC cells using growth curves, cell cycle analysis, and immunoblotting. Using an orthotopic mouse model, we determined the antitumor effects of sorafenib in vivo. Results: The concentration needed for 50% growth inhibition (GI(50)) by sorafenib was 0.14 mu mol/L for the PTC cells with the RET/PTC1 rearrangement, and 2.5 mu mol/L for PTC cells with a BRAF mutation, both readily achievable serum concentrations. After 3 weeks of oral administration of sorafenib (80 mg/kg/d) in mice, small (94% reduction compared with controls) or no tumor growth was detected in mice inoculated with PTC cells bearing the RET/PTC1 rearrangement, whereas the tumor volume of the orthotopic tumor implants of PTC cells with a BRAF mutation was reduced 53% to 54% (as compared with controls). Conclusions: PTC cells carrying the RET/PTC1 rearrangement were more sensitive to sorafenib than PTC cells carrying a BRAF mutation. Because RET/PTC rearrangements are unique to thyroid carcinomas, our findings support the clinical evaluation of sorafenib for patients with PTC and the identification of patients most likely to respond to sorafenib treatment.
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