Abstract 1208: Combination effect of afatinib and BI836845, a humanized IGF ligand-neutralizing antibody, on EGFR-TKI-resistant NSCLC cells
Authors: Ohmori Tohru , Yamaoka Toshimitsu , Arata Satoru , Ohba Motoi , Murata Yasunori , Kishida Yasunari , Kusumoto Sojiro , Nakashima Masanao , Hirose Takashi , Ohnishi Tsukasa , Nishio Kazuto 
Published: July 2016

Abstract
Insulin-like growth factor (IGF) signaling is thought to have a role in the cancer progression and survival, and many carcinomas are known to overexpress IGF-1 receptor (IGF1R). Furthermore, it was clarified that IGF1R signaling contributes to EGFR-TKI resistance in NSCLC. IGF1R is thought to be a therapeutic target for cancer chemotherapy. Previously, we screened the combination effect of afatinib and various anticancer drugs on a panel of NSCLC cell lines including gefitinib-resistant and afatinib-resistant PC-9 cells which we established. As the result, the combination of afatinib and small molecule IGF1R-TKIs (BMS754807, NVP-ADW742) has shown the most cytotoxicity on wide variety cancer cells. However, these IGF1R-TKIs have cross-reactivity to insulin receptor and, as a result, are known to cause hyperglycemia. Moreover, a phase III trial of the combination chemotherapy between erlotinib and IGF1R specific antibody, figitumumab, in advanced nonadenocarcinoma NSCLC patients (ADVIGO 1018)was closed early because of futility and an increased incidence of serious adverse events.
BI836845 is a humanized IGF ligand-neutralizing antibody which is neutralizing both IGF-1 and IGF-2. The proliferation of several cell lines was reported to be potently inhibited by BI 836845 with lower than 100 μg/ml EC50 values. This antibody is thought to be a substitute approach to inhibit IGF1R signaling pathway other than previous IGF1R-TKIs. We evaluated the combination effect of afatinib and BI836845 on the same NSCLC panel by MTS assay. BI836845 had only a limited cytotoxicity by itself. The combination of afatinib and BI836845 had additive or synergistic cytotoxicity on most of the NSCLC cell lines including EGFR-TKIs-resistant cells except the cells overexpressing c-Met or expressing K-ras mutation. This combination significantly inhibited both EGFR and IGF1R autophosphorylation and their downstream signaling, especially Akt/mTOR pathway, as compared with each singular usage. These combination effects were attenuated when BI836845 combined with erlotinib. Since BI836845 cross-react to rodent IGFs, we examined pharmacological activity of this combination using SCID mice xenograft mode. The mice bearing tumor were given 6 mg/kg afatinib (5 times/week, p.o.) and 200 mg/kg BI836845 (1 time/week, i.p.) for 8 weeks. This combination synergistically inhibited afatinib-resistant tumor (PC-9Afa1, PC-9Afa2) and gefitinib-resistant tumor (PC-9ZD, expressed T790M mutant EGFR). This BI836845 administration completely inhibited IGFs activity in the mice serum without alteration of blood sugar level and insulin concentration. Though growth rate of the treated mice was slightly reduced, body weight loss and other serious adverse events were not observed.
From these observations, this combination chemotherapy is thought to be a potential therapeutic strategy for NSCLC.
Citation Format: Tohru Ohmori, Toshimitsu Yamaoka, Satoru Arata, Motoi Ohba, Yasunori Murata, Yasunari Kishida, Sojiro Kusumoto, Masanao Nakashima, Takashi Hirose, Tsukasa Ohnishi, Kazuto Nishio. Combination effect of afatinib and BI836845, a humanized IGF ligand-neutralizing antibody, on EGFR-TKI-resistant NSCLC cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1208.