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402740 | New Interpretation | 01/22/2019 1:35 PM |
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Tier 2InterpretationFBXW7 is a tumor suppressor gene responsible for the degradation of several proto-oncogenes. mTOR is one of the substrates of FBXW7-mediated protein degradation, and loss of function of FBXW7 increases the levels of total and activated mTOR. FBXW7 R505C lies within the WD4 repeat region and confers a loss of FBXW7-substrate interaction and impairs substrate degradation by FBXW7, resulting in sustained NICD and MYC expression. Preclinical data have suggested that inactivating mutations of FBXW7 could predict sensitivity to the mTOR inhibitor rapamycin. A single study has reported only limited activity in phase I trials using mTOR inhibitors in patients with advanced cancers including colorectal cancer. The clinical utility remains unknown.
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Citations- Uniprot.org
- O'Neil J, et al. FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. J Exp Med. 2007 Aug 6;204(8):1813-24.
- Jardim DL, Wheler JJ, Hess K, et al. FBXW7 Mutations in Patients with Advanced Cancers: Clinical and Molecular Characteristics and Outcomes with mTOR Inhibitors. Li JJ, ed. PLoS ONE. 2014;9(2):e89388.
- Mao JH, Kim IJ, Wu D, Climent J, Kang HC, et al. (2008) FBXW7 targets mTOR for degradation and cooperates with PTEN in tumor suppression. Science 321: 1499--1502.
- Wang Y, Liu Y, Lu J, Zhang P, Wang Y, et al. (2013) Rapamycin inhibits FBXW7 loss-induced epithelial-mesenchymal transition and cancer stem cell-like characteristics in colorectal cancer cells. Biochem Biophys Res Commun.
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Last updated: 2019-01-22 18:35:33 UTC
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