Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus

Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and hyperactivation of 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 current 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 (28.6%) patient-derived HCC xenografts. TSC2 mutations and deletions are likely to be the underlying cause of TSC2 loss in HCC cell lines, xenografts, and primary tumors for most cases. We further demonstrated that TSC2-null HCC cell lines and xenografts had elevated mTOR signaling and, more importantly, were significantly more sensitive to RAD001/everolimus, an mTORC1 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 immunohistochemistry assay and identified 15 of 139 (10.8%) samples with low to undetectable levels of TSC2. Although the sample size is too small for formal statistical analysis, TSC2-null/low tumor patients who received everolimus tended to have longer overall survival than those who received placebo. Finally, we performed an epidemiology survey of more than 239 Asian HCC tumors and found the frequency of TSC2 loss to be approximately 20% in Asian HBV þ HCC. Taken together, our data strongly argue that TSC2 loss is a predictive biomarker for the response to everolimus in HCC patients. Mol Cancer Ther; 14(5); 1224-35. Ó2015 AACR.

Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

“…Germline mutations in either TSC1 or TSC2 result in the development of benign tumors (hamartomas) due to hyperactive mTORC1 signaling, which, however, usually does not result in malignancy. Moreover, loss of function of either TSC1 or TSC2 is rarely found in malignant tumors (Mieulet & Lamb, 2010) with some known exceptions like somatic mutations of TSC1 in bladder cancer (Pymar et al , 2008) or TSC2 in hepatocellular carcinoma's (Huynh et al , 2015). Therefore, retaining functional TSC1/2‐mTORC1 regulation may be beneficial for certain cancer cells (Mieulet & Lamb, 2010).…”

Phosphorylation of mTOR Ser2481 is a key target limiting the efficacy of rapalogs for treating hepatocellular carcinoma

“…We assessed previously reported mechanisms that account for the relatively higher sensitivities to mTORC1 inhibitors of the eight HCC cell lines [17–20]. TSC-1 and -2 are negative regulators of mTORC1, and knockdown of their expression induces constitutive activation of the mTORC1 pathway [17].…”

“…For example, the loss of TSC-2 predicts the response to an mTORC1 inhibitor [20], and mTORC1 inhibits p27 expression in close association with sensitivity to mTORC1 inhibitors [18]. However, it is unclear whether such changes of TSC-2 or p27 expression or both are involved in hypersensitivity to rapalogs of these HCC cell lines (Supplementary Figure S1).…”

Advanced Hepatocellular Cancer: the Current State of Future Research

“…TSC2-null/low tumor patients who received everolimus tended to have longer OS than those who had TSC2-null/low HCC that received placebo or those TSC expressing HCCs who were treated with everolimus. These data are limited given the small sample size but are hypothesis generating and suggest that TSC2 loss may be an important predictive biomarker for clinical [56] benefit to everolimus in HCC patients [60]. The hepatocyte growth factor (HGF)-MET axis has been implicated as a key player in hepatocarcinogenesis based on preclinical work and as such is another logical target for HCC drug development [61][62][63][64][65][66][67].…”