Abstract 5473: Anti-EGFR monoclonal antibody nimotuzumab enhances temozolomide-induced growth suppression of mutant EGFR expressing glioma xenografts.

Abstract

Abstract A mutant form of EGFR, EGFRvIII or ΔEGFR, is common in glioblastoma (GBM) conferring enhanced tumorigenic activity as well as resistance to chemotherapeutic drugs. Nimotuzumab, a humanized monoclonal EGFR antibody, has been shown to exert a modest activity in patients with GBM, but its specific activity against ΔEGFR has not been fully investigated. We treated human glioma cells overexpressing either wild-type (wt) EGFR or ΔEGFR with nimotuzumab with or without temozolomide (TMZ). Nimotuzumab treatment resulted in reduction in tyrosine phosphorylation at C-terminal of ΔEGFR more preferentially than that of wtEGFR, albeit to a lesser extent than tyrosine kinase inhibitor AG1478. Nimotuzumab-induced EGFR tyrosine dephosphorylation was associated with a decrease in AKT phosphorylation, suggesting suppression of downstream signaling pathways. In animal models, growth of subcutaneous xenografts was suppressed by TMZ, but was not affected by nimotuzumab monotreatment. However, antitumor activity was synergistically enhanced when TMZ was combined with nimotuzumab in both U87MG.ΔEGFR and LNZ308.ΔEGFR xenografts, while such an effect was limited in wtEGFR-overexpressing xenografts. Similarly, compared with nimotuzumab or TMZ monotherapy, the combination treatment of TMZ with nimotuzumab significantly elongated survival of mice bearing intracerebral xenografts derived from U87MG.ΔEGFR (p < 0.001, logrank test), and U87MG.wtEGFR to a lesser extent (p = 0.006). These anti-tumor effects by the combination treatment were associated with a decreased proliferation rate and an increase in apoptosis rate in treated xenografts. The U87MG.ΔEGFR intracerebral tumors which had re-grown after the combination treatment with TMZ and nimotuzumab (“escapers”) exhibited an increase expression of MGMT as well as a decrease in mismatch repair (MMR) proteins, MSH6 and MLH1. The reduction of MMR expression was further retained in subcultured escaper cells. These expression changes were not observed in xenografts treated with any of vehicles or monotherapies. These results suggest that nimotuzumab has antitumor activity against mutant EGFR-expressing glioma in vivo when combined with TMZ, and the resistance to this combination treatment might involve expression change of both MGMT and MMR. Citation Format: Motoo Nagane, Yusuke Nitta, Saki Shimizu, Yukiko Shishido-Hara, Yoshiaki Shiokawa. Anti-EGFR monoclonal antibody nimotuzumab enhances temozolomide-induced growth suppression of mutant EGFR expressing glioma xenografts. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5473. doi:10.1158/1538-7445.AM2013-5473 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.