Lexatumumab (TRAIL-receptor 2 mAb) induces expression of DR5 and promotes apoptosis in primary and metastatic renal cell carcinoma in a mouse orthotopic model

Cancer Lett. 2007 Jun 18;251(1):146-57. doi: 10.1016/j.canlet.2006.11.013. Epub 2006 Dec 20.


Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a variety of tumorigenic and transformed cell lines but not in many normal cells. Hence, TRAIL-agonist compounds have the potential of being excellent cancer therapeutic agents with minimal cytotoxicity. Here, we examine the efficacy of the TRAIL-receptor 2 agonist, lexatumumab (Human Genome Sciences, Inc., Rockville, MD), and identify molecular pathways that differentiate between lexatumumab-sensitive and lexatumumab-resistance renal cancer cells. In an orthotopic metastatic mouse model, we first demonstrate that lexatumumab was effective in reducing the tumor burden of primary and metastatic lexatumumab-sensitive xenografts. We demonstrate that lexatumumab-sensitive cells were capable of triggering both the extrinsic and the intrinsic apoptotic pathways as demonstrated by caspase 8 and caspase 9 activations, respectively, after treatment with lexatumumab. In addition, expression of c-FLIP(L) protein, an important regulator of TRAIL-induced apoptosis, decreased, while expression of the TRAIL-receptor 2, DR5, increased. This study serves as a pre-clinical model for using TRAIL-like therapies for patients with advanced RCC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology*
  • Apoptosis / drug effects*
  • Blotting, Western
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism
  • Carcinoma, Renal Cell / pathology
  • Carcinoma, Renal Cell / prevention & control*
  • Carcinoma, Renal Cell / secondary
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Humans
  • Immunohistochemistry
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / pathology
  • Kidney Neoplasms / prevention & control*
  • Mice
  • Mice, Nude
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / immunology
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays*


  • Antibodies, Monoclonal
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • lexatumumab