Sorafenib Sensitizes Solid Tumors to Apo2L/TRAIL and Apo2L/TRAIL Receptor Agonist Antibodies by the Jak2-Stat3-Mcl1 Axis.

TitleSorafenib Sensitizes Solid Tumors to Apo2L/TRAIL and Apo2L/TRAIL Receptor Agonist Antibodies by the Jak2-Stat3-Mcl1 Axis.
Publication TypeJournal Article
Year of Publication2013
AuthorsAbdulghani J, Allen JE, Dicker DT, Liu YY, Goldenberg D, Smith CD, Humphreys R, El-Deiry WS
JournalPloS one
Volume8
Issue9
Paginatione75414
Date Published2013
Abstract

Approximately half of tumor cell lines are resistant to the tumor-selective apoptotic effects of tumor necrosis factor-related apoptosis-inducing ligand (Apo22L/TRAIL). Previously, we showed that combining Apo2L/TRAIL with sorafenib, a multikinase inhibitor, results in dramatic efficacy in Apo2L/TRAIL-resistant tumor xenografts via inhibition of Mcl-1. Soluble Apo2L/TRAIL is capable of binding to several surface receptors, including the pro-apoptotic death receptors, DR4 and DR5, and decoy receptors, DcR1 and DcR2. Monoclonal antibodies targeting either of these death receptors are being investigated as antitumor agents in clinical trials. We hypothesized that sorafenib and Apo2L/TRAIL or Apo2L/TRAIL death receptor agonist (TRA) antibodies against DR4 (mapatumumab) and DR5 (lexatumumab) will overcome resistance to Apo2L/TRAIL-mediated apoptosis and as increase antitumor efficacy in Apo2L/TRAIL-sensitive solid tumors.

DOI10.1371/journal.pone.0075601
Alternate JournalPLoS ONE