FBXW7 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.