P1.03-17 Functional Mechanism of GLDC Gene Alternative Splicing in Non-Small Cell Lung Cancer

Abstract

angiogenesis. However, the underlying molecular mechanisms and predictive biomarker of Anlotinib are still unclear. Method: 437 patients with advanced NSCLC enrolled in clinical study, and 294 patients received Anlotinib therapy. Retrospectively analysis of the Anlotinibadministrated 294 NSCLC patients was performed to screen out underlying biomarker for Anlotinib-responsive patients. Transcriptome and functional assays were performed to understand the anti-tumor molecular mechanism of Anlotinib in vitro. CCL2 levels and their roles in angiogenesis were evaluated by ELISA detection, RT-qPCR quantification, and immunofluorescence assay, in vivo. Changes in serum CCL2 levels were analyzed to reveal the correlation of Anlotinib response between responders and non-responders. Result: Anlotinib therapy is more beneficial to prolong OS for NSCLC patients harboring positive driver gene mutations, especially for patients harboring EGFR T790M mutation. Moreover, our data indicated that Anlotinib-induced cell viability downregulation, cell apoptosis induction, cell invasion inhibition, cell cycle arrest, and cell migration inhibition are associated with CCL2 levels in vitro. We demonstrated that Anlotinib inhibits angiogenesis of NCI-H1975 derived xenografts model via inhibiting CCL2 in vivo. Lastly, we found that Anlotinib-induced serum CCL2 level decreases are associated with the benefits of PFS and OS, in refractory advanced NSCLC patients (n ¼ 28). Conclusion: Our study reports a novel anti-angiogenesis mechanism of Anlotinib via inhibiting CCL2 in NCI-H1975 derived xenografts model, and suggests the changes in serum CCL2 levels may be used to monitor and predict clinical outcome in Anlotinib-administered refractory advanced NSCLC patients. The biomarker of serum CCL2 alteration may guide precision therapy of Anlotinib for NSCLC patients at third-line or over third-line.