Synergistic anticancer activity of arsenic trioxide with erlotinib is based on inhibition of EGFR-mediated DNA double strand break repair
Menée in vitro et in vivo, cette étude suggère l'efficacité d'un traitement combinant le trioxyde d'arsenic et une thérapie ciblée sur EGFR pour les tumeurs solides sans mutation du gène EGFR
Arsenic trioxide (ATO), one of the oldest remedies used in traditional medicine, was recently rediscovered as anticancer drug and approved for treatment of relapsed acute promyelocytic leukemia. However, its activity against non-hematologic cancers is rather limited so far. Here, we show that inhibition of ATO-mediated epidermal growth factor receptor (EGFR) activation can be used to potently sensitize diverse solid cancer types against ATO. Thus, combination of ATO and the EGFR inhibitor erlotinib exerted synergistic activity against multiple cancer cell lines. Subsequent analyses revealed that this effect was based on the blockade of ATO-induced EGFR phosphorylation leading to more pronounced G2/M arrest as well as enhanced and more rapid induction of apoptosis. Comparable ATO-sensitizing effects were also found with PI3K/AKT und MEK inhibitors suggesting an essential role of the EGFR-mediated downstream signaling pathway in cancer cell protection against ATO. H2AX staining and comet assay revealed that erlotinib significantly increases ATO-induced DNA double strand breaks well in accordance with a role of the EGFR signaling axis in DNA damage repair. Indeed, EGFR inhibition led to downregulation of several DNA double strand break repair proteins like Rad51 and Rad50 as well as reduced phosphorylation of BRCA1. Finally, the combination treatment of ATO and erlotinib was also distinctly superior to both mono-treatments against the notoriously therapy-resistant human A549 lung cancer and the orthotopic p31 mesothelioma xenograft model in vivo. In conclusion, this study suggests that combination of ATO and EGFR inhibitors is a promising therapeutic strategy against various solid tumors harboring wild-type EGFR.
http://mct.aacrjournals.org/content/early/2013/04/02/1535-7163.MCT-13-0065.abstract