Abstract 7257: Identification of KDR as a novel effector downstream of ETS variant transcription factor 4 in NSCLC

Abstract The ETS family comprises transcription factors characterized by a highly conserved DNA-binding domain that recognizes a central GGA(A/T) motif. Among these, ETV4, the predominant member of the PEA3 subfamily, has been strongly associated with advanced disease stage and poor prognosis in multiple malignancies, including non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC), largely through its MAPK-dependent transcriptional activity. Despite its clinicopathologic significance, the downstream effectors and genome-scale regulatory circuitry governed by ETV4 remain incompletely defined. Here, we aimed to define the ETV4-driven transcriptional landscape. We identified KDR/VEGFR2 as a direct ETV4-promoted target, with ETV4 overexpression markedly elevating KDR transcripts and protein levels. Through chromatin immunoprecipitation and complementary binding assays, we demonstrated physical occupancy of ETV4 at the KDR promoter. Although KDR/VEGFR2 is classically characterized as an endothelial receptor that amplifies angiogenic signaling, accumulating evidence indicates that cancer cell-intrinsic KDR supports vasculogenic mimicry and aggressive structural remodeling through VEGF/VEGFR2 paracrine and autocrine circuits. Pharmacologic suppression of ETV4 significantly attenuated KDR expression and impaired epithelial-mesenchymal transition, migration, and invasion, phenotypes that were recapitulated by genetic silencing of either ETV4 or KDR. Collectively, these findings define a previously unrecognized transcriptional axis in which ETV4 directly activates KDR/VEGFR2 to potentiate malignant behavior, positioning the ETV4-KDR pathway as a targetable therapeutic vulnerability across ETV4-high tumors. Citation Format: Su Hyeon Yu, Jiyoon Kang, Ji Won Kim. Identification of KDR as a novel effector downstream of ETS variant transcription factor 4 in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7257.