Abstract 1101: Intercellular transfer of exosomal wild type EGFR triggers osimertinib resistance in non-small cell lung cancer

Epidermal growth factor receptor (EGFR)-mutated lung cancer constitutes a major subgroup of non-small cell lung cancer (NSCLC) and osimertinib is administrated as first-line treatment. However, most patients with osimertinib treatment eventually relapse within one year. The underlying mechanisms of osimertinib resistance remain largely unexplored. In this study, we found that osimertinib resistance could be triggered by the intercellular transfer of wild type EGFR protein encapsulated in exosomes from osimertinib-insensitive NSCLC cells to EGFR-mutated osimertinib-sensitive cells and then the activation of PI3K/AKT and MAPK signaling pathways both in vitro and in vivo. Importantly, osimertinib significantly increased the formation and secretion of exosomes linked to the upregulation of a Rab GTPase (RAB17). These results demonstrate the intercellular transfer of exosomal wild type EGFR maybe a novel resistant mechanism of osimertinib. These findings provide a proof of concept for targeting exosomes to prevent and reverse the osimertinib resistance. Citation Format: Shaocong Wu, Min Luo, Kenneth K. To, Jianye Zhang, Chaoyue Su, Hong Zhang, Sainan An, Fang Wang, Da Chen, Li-Wu Fu. Intercellular transfer of exosomal wild type EGFR triggers osimertinib resistance in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1101.