Abstract P18: RHBDL2 PROMOTES NON-SMALL CELL LUNG CANCER METASTASIS AND OSIMERTINIB RESISTANCE BY ACTIVATING RAS/MEK/ERK SIGNALING PATHWAY THROUGH INTERACTION WITH FGFR

Abstract Non-small cell lung cancer (NSCLC) is a highly malignant form of cancer, distinguished by prompt metastasis, restricted response to chemotherapy, and unfavorable prognosis. As a result, there is an imperative requirement to investigate novel therapeutic approaches for NSCLC. Rhomboid-like protein 2 (RHBDL2) is overexpressed in various tumor cells and is associated with poor prognosis. However, the relevance of RHBDL2 to NSCLC remains unclear. This study aims to investigate the potential role of RHBDL2 as a diagnostic and prognostic biomarker for NSCLC, as well as its biological functions and molecular mechanisms in NSCLC. We found that RHBDL2 was highly expressed in human NSCLC cells and tissues, and was significantly correlated with distant metastasis and poor survival of NSCLC patients. Gain- and loss-of-function assays showed that RHBDL2 could accelerate NSCLC metastasis in vitro and in vivo. KEGG/GO enrichment analysis identified that the function of RHBDL2 was significantly associated with the activity of RAS signaling pathway. RNA-Seq results also suggested that RHBDL2 might be involved in the activation of the RAS/MEK/ERK signaling pathway. ERK1/2 inhibitor Ravoxertinib could partially restore the metastatic ability of NSCLC cells mediated by RHBDL2. CO-IP/MS results suggested that RHBDL2 interacted with FGFR. GST-pulldown assay confirmed the above findings. RHBDL2 could directly interact with FGFR and affect its phosphorylation, and promote NSCLC cell migration by activating the downstream RAS/MEK/ERK signaling pathway. In addition, we also found that RHBDL2 was involved in osimertinib resistance through FGFR/RAS pathway. Our study results indicate that RHBDL2 promotes NSCLC cell migration and osimertinib resistance by interacting with FGFR and thereby activating the RAS/MEK/ERK signaling pathway. Moreover, it can serve as a novel diagnostic and prognostic biomarker for NSCLC patients. Citation Format: Jun Deng, Jia-jia Qin, Neng-ming Lin. RHBDL2 PROMOTES NON-SMALL CELL LUNG CANCER METASTASIS AND OSIMERTINIB RESISTANCE BY ACTIVATING RAS/MEK/ERK SIGNALING PATHWAY THROUGH INTERACTION WITH FGFR abstract. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84 (8Suppl): Abstract nr P18.