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Loss of Tuberous Sclerosis Complex 2 (TSC2) Confers Sensitivity to mTOR Inhibitor Everolimus in Hepatocellular Carcinoma

Huynh, Hung, Hao, Huaixiang, Chan, Stephen L. , Chen, David, Ong, Richard, Soo, Khee Chee, Pochanard, Panisa, Yang, David, Ruddy, David, Liu, Manway, Derti, Adnan, Balak, Marissa, Palmer, Michael, Wang, Yan, Lee, Benjamin, Sellami, Dalila, Zhu, Andrew, Schlegel, Robert and Huang, Alan (2015) Loss of Tuberous Sclerosis Complex 2 (TSC2) Confers Sensitivity to mTOR Inhibitor Everolimus in Hepatocellular Carcinoma. Mol Cancer Ther..


Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and hyper-activation of mammalian target of rapamycin (mTOR) signaling plays a pivotal role in HCC tumorigenesis. Tuberous Sclerosis Complex (TSC), a heterodimer of TSC1 and TSC2, functions as a negative regulator of mTOR signaling. In the present study, we discovered that TSC2 loss of function is common in HCC. TSC2 loss was found in 4 of 8 HCC cell lines and 8 of 28 (28.5%) patient-derived HCC xenografts. TSC2 mutations and deletions are likely to be the underlying cause of TSC2 loss in HCC cell lines, xenografts and tumors for most cases. We further demonstrated that TSC2-null HCC cell lines and xenografts have elevated mTOR signaling and, more importantly, were significantly more sensitive to RAD001 (everolimus), an mTOR inhibitor. These preclinical findings led to the analysis of TSC2 status in HCC samples collected in the EVOLVE-1 clinical trial of everolimus. Using an optimized IHC assay we developed, 15 samples with low to undetectable levels of TSC2 (10.8%) were identified (5 in the placebo arm and 10 in the everolimus arm). Although the sample size lacked power to demonstrate statistical significance, TSC2-null/low tumor patients who received everolimus had noticeably longer overall survival than those who received placebo. We also observed that TSC2 loss is rare in Caucasian samples compared to Asian samples. Therefore, we performed an epidemiology survey of more than 239 Asian HCC tumors. The frequency of TSC2 loss is estimated to be around 20% in Asian HBV+ HCC, which accounts for nearly half of HCC malignancies in the world. Taken together, our data strongly argue that TSC2 loss is a predictive biomarker for the sensitivity to everolimus in HCC patients and can be applied as a robust selection biomarker for mTOR inhibitor clinical trials.

Item Type: Article
Date Deposited: 26 Apr 2016 23:46
Last Modified: 26 Apr 2016 23:46


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