Sorafenib sensitizes solid tumors to Apo2L/TRAIL and Apo2L/TRAIL receptor agonist antibodies by the Jak2-Stat3-Mcl1 axis

• Published in: PloS one 2013-09, Vol.8 (9), p.e75414
• Main Authors: Abdulghani, Junaid, Allen, Joshua E, Dicker, David T, Liu, Yingqiu Yvette, Goldenberg, David, Smith, Charles D, Humphreys, Robin, El-Deiry, Wafik S
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal - pharmacology; Anticancer properties; Antitumor activity; Antitumor agents; Apoptosis; Apoptosis - drug effects; Biotechnology; Blotting, Western; Cancer therapies; Cell death; Cell Line, Tumor; Chemotherapy; Clinical trials; Colon; Cyclin D1; Cyclin D2; Death receptors; Drug Synergism; Growth factors; Humans; Immunoglobulins; Immunohistochemistry; In Situ Nick-End Labeling; Janus kinase 2; Janus Kinase 2 - metabolism; Kinases; Ligands; Liver; Liver cancer; Mcl-1 protein; Medical research; Monoclonal antibodies; Mortality; Neoplasms - drug therapy; Niacinamide - analogs & derivatives; Niacinamide - pharmacology; Phenylurea Compounds - pharmacology; Prostate; Receptors; Receptors, TNF-Related Apoptosis-Inducing Ligand - agonists; Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism; Signal Transduction - drug effects; Signaling; Solid tumors; Stat3 protein; STAT3 Transcription Factor - metabolism; Thyroid; TNF-Related Apoptosis-Inducing Ligand - metabolism; TRAIL protein; Tumor cell lines; Tumor necrosis factor-TNF; Tumors; Xenografts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0075414

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. We found that Apo2L/TRAIL or TRA antibodies combined with sorafenib synergistically reduce cell growth and increase cell death across a panel of solid tumor cell lines in vitro. This panel included human breast, prostate, colon, liver and thyroid cancers. The cooperativity of these combinations was also observed in vivo, as measured by tumor volume and TUNEL staining as a measure of apoptosis. We found that sorafenib inhibits Jak/Stat3 signaling and downregulates their target genes, including cyclin D1, cyclin D2 and Mcl-1, in a dose-dependent manner. The combination of sorafenib with Apo2L/TRAIL or Apo2L/TRAIL receptor agonist antibodies sensitizes Apo2L/TRAIL-resistant cells and increases the sensitivity of Apo2L/TRAIL-sensitive cells. Our findings demonstrate the involvement of the Jak2-Stat3-Mcl1 axis in response to sorafenib treatment, which may play a key role in sorafenib-mediated sensitization to Apo2L/TRAIL.