Vgf As A Theranostic Marker In Neuroendocrine Lung Cancer

Activating EGFR mutations are predictive markers for response in lung cancer patients under the treatment of EGFR-tyrosine kinase inhibitors (TKIs), whereas acquired resistance to EGFR-TKIs inevitably occurs in patients. Neuroendocrine transformation is one of the mechanisms behind the development of acquired resistance to EGFR-TKIs. In this study, we report that VGF, a secreted factor highly expressed in neurons and neuroendocrine tissues, is a potential theranostic marker in neuroendocrine lung tumors. Gene expression profiling analysis revealed that VGF levels were elevated during the differentiation of neuronal stem cells to neurons with surged H3K27ac modification at the VGF locus. We observed that VGF was highly expressed in lung neuroendocrine cancer cells. Moreover, VGF expression was low in lung adenocarcinoma but was enriched during EGFR-TKI selection. Correlation analysis showed that VGF was positively associated with chromogranin A, chromogranin B, and synaptophysin expression in lung tumors. ChIP-qPCR assays showed that the signal of H3K27ac modification at the VGF locus was increased in EGFR-TKI resistant cells compared to their sensitive counterparts. Clonogenic analysis and annexin-V staining assays revealed that VGF silencing attenuated cellular grown with increased apoptosis in neuroendocrine lung cancer cells as well as in EGFR-TKI resistant cells, indicating the potential of VGF as a therapeutic target. Kaplan-Meier analysis showed that high VGF expression predicted poor survival outcome in patients with lung tumors. Our findings provide an insight into the oncogenic role of VGF and suggest the potential of VGF as a theranostic for lung cancer. Citation Format: Li-Hao Yang, Chia-Cherng Yu, Yu-Ting Chou. VGF as a theranostic marker in neuroendocrine lung cancer [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 2931.