Lexatumumab (TRAIL-receptor 2 mAb) induces expression of DR5 and promotes apoptosis in primary and metastatic renal cell carcinoma in a mouse orthotopic model.
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.
Zhang
Liang
L
Division of Urologic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
Zhang
Xiaoping
X
Barrisford
Glen W
GW
Olumi
Aria F
AF
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000473:pathology / Q000517:prevention & control* / Q000556:secondary; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008819:Mice, Nude; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C510234:lexatumumab