Oral recombinant methioninase increases TRAIL receptor-2 expression to regress pancreatic cancer in combination with agonist tigatuzumab in an orthotopic mouse model

  • Cancer Lett. 2020 Nov 1;492:174-184. doi: 10.1016/j.canlet.2020.07.034.
Jun Yamamoto  1 ,  Kentaro Miyake  1 ,  Qinghong Han  2 ,  Yuying Tan  2 ,  Sachiko Inubushi  3 ,  Norihiko Sugisawa  3 ,  Takashi Higuchi  3 ,  Yoshihiko Tashiro  3 ,  Hiroto Nishino  3 ,  Yuki Homma  4 ,  Ryusei Matsuyama  4 ,  Sant P Chawla  5 ,  Michael Bouvet  6 ,  Shree Ram Singh  7 ,  Itaru Endo  8 ,  Robert M Hoffman  9
Affiliations
  • 1. AntiCancer Inc, San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA; Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
  • 2. AntiCancer Inc, San Diego, CA, USA.
  • 3. AntiCancer Inc, San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA.
  • 4. Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
  • 5. Sarcoma Oncology Center, Santa Monica, CA, USA.
  • 6. Department of Surgery, University of California, San Diego, CA, USA.
  • 7. Basic Research Laboratory, National Cancer Institute, Frederick, MD, USA. Electronic address: [email protected].
  • 8. Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan. Electronic address: [email protected].
  • 9. AntiCancer Inc, San Diego, CA, USA; Department of Surgery, University of California, San Diego, CA, USA. Electronic address: [email protected].
PMID: 32739322 DOI: 10.1016/j.canlet.2020.07.034
Abstract

Methionine addiction is a fundamental and general hallmark of Cancer. Gene expression analysis showed that methionine restriction (MR) of methionine-addicted Cancer cells increases TNF-related apoptosis-induced ligand receptor-2 (TRAIL-R2) expression. Here, we determined the effects of MR on TRAIL-R2 targeted therapy in pancreatic Cancer by the TRAIL-R2 agonist tigatuzumab. Human pancreatic Cancer cell lines were cultured in control or methionine-free medium. The effects of MR on TRAIL-R2 expression and sensitivity to tigatuzumab were evaluated in vitro. An orthotopic pancreatic Cancer mouse model was established to evaluate the efficacy of MR using oral recombinant methioninase (o-rMETase), and the efficacy of tigatuzumab and their combination. MR enabled tigatuzumab-induced Apoptosis, by increasing TRAIL-R2 expression in pancreatic Cancer cells in vitro. The protein expression level of the melanoma-associated antigen MAGED2, which reduces TRAIL-R2 expression, was decreased by MR. In the orthotopic pancreatic Cancer mouse model, o-rMETase increased TRAIL-R2 expression level in the tumors and enabled the antitumor efficacy of tigatuzumab. MR, effected by o-rMETase, enabled the efficacy of the TRAIL-R2 agonist tigatuzumab by increasing TRAIL-R2 expression in pancreatic Cancer. Our results suggest that o-rMETase has clinical potential for treating pancreatic Cancer.

Keywords
Methioninase; Methionine restriction; Pancreatic cancer; TRAIL-R2; Tigatuzumab.
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