Abstract 3263: VEGFA mediates traditional EGFR-TKI resistance in non-small cell lung cancer with EGFR exon 20 insertions

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Abstract Background: Epidermal growth factor receptor (EGFR) exon 20 insertions (Ex20ins) accounted for 4%-12% of EGFR mutations and showed primary resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) which is an urgent issue to be solved. In our previous studies, we found that antiangiogenetic therapy had certain advantages for patients with Ex20ins in the real-world practice. Previous research showed the tumor microenvironment has been associated with resistance to targeted therapy in sensitive mutations. However, the mechanism of resistance of EGFR-TKIs and the advantage of antiangiogenetic therapy in patients with EGFR Ex20ins were still unclear. Methods: In this study, patients with EGFR exon 19 deletion (19del), exon 21 p.L858R (21L858R), and Ex20ins were collected to identify the efficacy of EGFR-TKIs. Stable cell lines expressing were established and used to compare signaling pathway activation. Matrigel angiogenesis assay was conducted in different cell lines. Next, we evaluated the efficacy of various treatments combined with antiangiogenetic agents or not in mouse models. Results: We collected 23 patients with EGFR sensitive mutations and Ex20ins, respectively, and found Ex20ins presented primary resistance to TKIs and poor survival outcomes. Based on the RNA sequence of stable cell lines, it was found that Ex20ins had a higher level of VEGFA expression and enriched in MAPK pathway compared to EGFR 19del and 21L858R. Immunohistochemical studies also revealed that a higher level of VEGFA expression was observed in a cohort of NSCLC patients with Ex20ins mutation compared with 19del or L858R. Matrigel angiogenesis assay has shown consistent result that Ex20ins promoted angiogenesis in vivo. Further experiments in mouse models identified that in the group of Osimertinib, mobocertinib alone, chemotherapy alone, mobocertinib or chemotherapy combination with bevacizumab, Osimertinib achieved the worst efficacy and additional utility of antiangiogenetic agents had a more favorable efficacy. Conclusion: Our study highlights the potential of VEGFA as a mechanism of resistance to EGFR-TKIs and induces immunosuppression microenvironment in NSCLC with Ex20ins. Furthermore, the findings suggested that antiangiogenetic therapy could be a promising therapeutic approach. Keywords: VEGFA, targeted therapy, resistance, EGFR exon 20 insertions, non-small cell lung cancer Citation Format: Yaning Yang, Chengming Liu, Guangjian Yang, Haiyan Xu, Siyu Lei, Yan Wang. VEGFA mediates traditional EGFR-TKI resistance in non-small cell lung cancer with EGFR exon 20 insertions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3263.