title: Loss of Tuberous Sclerosis Complex 2 (TSC2) as a Predictive Biomarker of Response to mTOR Inhibitor Treatment in Patients with Hepatocellular Carcinoma.
abstract: BACKGROUND
  Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death globally. Mechanistic target of rapamycin (mTOR) is frequently up-regulated in HCC and plays an important role in HCC tumorigenesis. Tumors with loss of tuberous sclerosis complex 2 (TSC2), a negative regulator of mTOR signaling, tend to respond well to mTOR inhibitors. We analyzed TSC2 expression status in Korean patients with HCC and evaluated the correlation between TSC2 loss and response to the mTOR inhibitor, everolimus.
  
  
  METHODS
  We retrospectively assessed 36 patients with advanced HCC who had received sorafenib at a single center in Korea between 2008 and 2014, and for whom tumor specimens were available for TSC2 immunohistochemical analysis (IHC). Three patient-derived tumor cell lines (PDCs) were analyzed by western blotting to determine TSC2 expression and drug sensitivity to mTOR.
  
  
  RESULTS
  Twelve of 36 patients (33.3%) showed low to undetectable levels of TSC2 expression. No significant differences were observed in progression-free survival (PFS) or overall survival with sorafenib treatment based on TSC2 expression status. Two patients were treated with everolimus after sorafenib failure; one patient, with moderate TSC2 expression, experienced stable disease with a PFS of 5.8 months; the other, with high TSC2 expression, experienced rapid progression. PDC models demonstrated that the TSC2-low HCC PDC line was significantly more sensitive to everolimus than the TSC2-high HCC PDC lines.
  
  
  CONCLUSIONS
  Loss of TSC2 may predict improved response to everolimus in HCC patients, but further studies are needed to confirm the predictive role of TSC2 expression for everolimus treatment.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Jinhyun
authors.initials: J
authors.lastname: Cho
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Jeeyun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Jusun
authors.initials: J
authors.lastname: Kim
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Seung Tae
authors.initials: ST
authors.lastname: Kim
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Sujin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Sun Young
authors.initials: SY
authors.lastname: Kim
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
authors.forename: Sang Yun
authors.initials: SY
authors.lastname: Ha
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Electronic address: ckpark@skku.edu.
authors.forename: Cheol-Keun
authors.initials: CK
authors.lastname: Park
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, Republic of Korea. Electronic address: hoylim@skku.edu.
authors.forename: Ho Yeong
authors.initials: HY
authors.lastname: Lim