Abstract 1874: Anti-VEGF therapy sensitizes EGFR/MET co-altered NSCLC cells to TKIs via inhibiting the VEGF/ERK/MET pathway

Abstract

Abstract Mesenchymal epithelial transition factor (MET) activation has been considered to mediate primary and acquired resistance to EGFR tyrosine kinase inhibitors (TKI) in epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC), but the mechanisms are not wholly clear. Meanwhile, the effective therapeutic strategy for these patients remains controversial. We previously presented a lung adenocarcinoma patient with dual EGFR-MET alterations benefited from bevacizumab + erlotinib as first-line treatment, achieving 13 months partial response (PR). PFS of another phase reached to 9 months with the combination of osimertinib + crizotinib + bevacizumab when disease proceeded due to increased MET copy number. Persistent PFS benefit was confirmed when the patient was administrated with different TKIs treatment in the presence of bevacizumab. However, the underlying mechanism remains elusive. Thus, we assumed that VEGF might be involved in the regulation of the MET signaling pathway and the addition of anti-VEGF therapy might be promising. In this study, we firstly confirmed whether MET overexpression alone might causally responsible for resistance to gefitinib treatment. Thus, we conducted in vitro forward genetic experiments, we took advantage of the EGFR-mutant lung cancer cell line PC-9, which had been shown to be sensitive to gefitinib. Ectopic overexpression of MET in PC-9 parental cells (PC-9/MET) was able to confer resistance to gefitinib by activating AKT and ERK signaling and sustaining proliferation.Meanwhile we got a gefitinib resistant EGFR mutant NSCLC cell line, HCC827 (HCC827-GR), which showing acquired MET amplification. Interestingly, we found that VEGF promoted cell survival and elicited adaptive resistance to gefitinib and crizotinib alone or in combination in MET transduced PC9-MET cells. This phenomenon also existed in HCC827-GR which harboring MET amplification. Importantly, addition of the VEGF inhibitor bevacizumab was able to restore partial sensitivity to gefitinib in both PC-9/MET and HCC827-GR cells while triple inhibition of EGFR, MET, and VEGF could suppresses the cell proliferation more remarkable. Moreover, we observed that VEGF could facilitate MET phosphorylation and activate several intracellular signaling pathways, including ERK, AKT, and Stat3. Then we pretreated cells with several specific kinase inhibitors, followed by treatment with VEGF. We found that VEGF-mediated up-regulation of MET depended on the ERK pathway and was independent of AKT and Stat3 pathways. These findings were further confirmed in human NSCLC Xenograft models. Addition of bevacizumab to TKIs resulted in stronger inhibition of tumor growth than TKI alone or TKIs combination treatment, by blocking both EGFR and MET signal transduction. In conclusion, bevacizumab + TKIs enhanced antitumor activity in NSCLC with EGFR/MET co-alteration through inhibition of the VEGF/ ERK/MET signaling axis. Citation Format: Qian Chu, Shanshan Huang, Yuan Gao, Jie Lin, Yuan Chen, Bo Zhu, Kongming Wu. Anti-VEGF therapy sensitizes EGFR/MET co-altered NSCLC cells to TKIs via inhibiting the VEGF/ERK/MET pathway [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1874.