Loss of Tuberous Sclerosis Complex 2 (TSC2) Is Frequent in Hepatocellular Carcinoma and Predicts Response to mTORC1 Inhibitor Everolimus.
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(+) HCC. Taken together, our data strongly argue that TSC2 loss is a predictive biomarker for the response to everolimus in HCC patients.
Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore. alan.huang@novartis.com cmrhth@nccs.com.sg.
Hung
H
Huynh
Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
Huai-Xiang
HX
Hao
State Key Laboratory in Oncology in South China, Department of Clinical Oncology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, PR China.
Stephen L
SL
Chan
Oncology Global Development, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
David
D
Chen
Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.
Richard
R
Ong
Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore.
Khee Chee
KC
Soo
Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
Panisa
P
Pochanard
Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
David
D
Yang
Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
David
D
Ruddy
Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
Manway
M
Liu
Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
Adnan
A
Derti
Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
Marissa N
MN
Balak
Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
Michael R
MR
Palmer
Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
Yan
Y
Wang
Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
Benjamin H
BH
Lee
Oncology Global Development, Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.
Dalila
D
Sellami
Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
Andrew X
AX
Zhu
Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
Robert
R
Schlegel
Oncology Translational Medicine, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts. alan.huang@novartis.com cmrhth@nccs.com.sg.
Alan
A
Huang
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D044466:Asian People / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics* / Q000821:virology; D045744:Cell Line, Tumor; D000068338:Everolimus / Q000627:therapeutic use*; D006509:Hepatitis B / Q000453:epidemiology* / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000821:virology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors; D009154:Mutation; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016896:Treatment Outcome; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D000970:Antineoplastic Agents; D046912:Multiprotein Complexes; C000624653:TSC2 protein, human; C000624654:Tsc2 protein, mouse; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D000068338:Everolimus; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases