Sym004, a novel anti-EGFR antibody mixture augments radiation response in human lung and head and neck cancers
Menée in vitro et à l'aide de xénogreffes, cette étude montre que Sym004, une préparation d'anticorps ciblant le récepteur EGFR, peut améliorer la réponse à une radiothérapie des cellules cancéreuses du poumon ou des voies aérodigestives supérieures
Sym004 represents a novel EGFR targeting approach comprised of a mixture of two anti-EGFR antibodies directed against distinct epitopes of EGFR. In contrast to single anti-EGFR antibodies, Sym004 induces rapid and highly efficient degradation of EGFR. In the current study, we examine the capacity of Sym004 to augment radiation response in lung cancer and head and neck (H&N) cancer model systems. We first examined the anti-proliferative effect of Sym004 and confirmed 40~60% growth inhibition by Sym004. Using clonogenic survival analysis, we identified that Sym004 potently increased cell kill by up to 10-fold following radiation exposure. A significant increase of γH2AX foci resulting from DNA double strand breaks was observed in Sym004-treated cells following exposure to radiation. Mechanistic studies further demonstrated that Sym004 enhanced radiation response via induction of cell cycle arrest followed by induction of apoptosis and cell death reflecting inhibitory effects on DNA damage repair. The expression of several critical molecules involved in radiation-induced DNA damage repair were significantly inhibited by Sym004, including DNAPK, NBS1, RAD50, and BRCA1. Using single and fractionated radiation in human tumor xenograft models, we confirmed that the combination of Sym004 and radiation resulted in significant tumor regrowth delay and superior anti-tumor effects compared to treatment with Sym004 or radiation alone. Taken together, these data reveal the strong capacity of Sym004 to augment radiation response in lung and H&N cancers. The unique action mechanism of Sym004 warrants further investigation as a promising EGFR targeting agent combined with radiotherapy in cancer therapy.
http://mct.aacrjournals.org/content/early/2013/10/15/1535-7163.MCT-13-0587.abstract