1. Academic Validation
  2. Intercellular transfer of exosomal wild type EGFR triggers osimertinib resistance in non-small cell lung cancer

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

  • Mol Cancer. 2021 Jan 18;20(1):17. doi: 10.1186/s12943-021-01307-9.
Shaocong Wu 1 Min Luo 1 Kenneth K W To 2 Jianye Zhang 3 Chaoyue Su 1 3 Hong Zhang 1 Sainan An 1 Fang Wang 1 Da Chen 1 Liwu Fu 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine; Guangdong Esophageal Cancer Institute; Sun Yat-sen University Cancer Center, Guangzhou, 510060, People's Republic of China.
  • 2 School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Room 801N, Area 39, Lo Kwee-Seong Integrated Biomedical Sciences Building, Shatin, New Territories, Hong Kong, SAR, China.
  • 3 School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
  • 4 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine; Guangdong Esophageal Cancer Institute; Sun Yat-sen University Cancer Center, Guangzhou, 510060, People's Republic of China. [email protected].
Abstract

Background: 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.

Methods: Exosomes isolation was performed by differential centrifugation. Co-culture assays were conducted to explore the alteration of drug sensitivity by cell viability and Apoptosis assays. Immunofluorescence and flow cytometry were performed to visualize the formation or absorption of exosomes. Exosomes secretion was measured by Nanoparticle Tracking Analysis or ELISA. The xenograft tumor model in mice was established to evaluate the effect of exosomes on osimertinib sensitivity in vivo.

Results: Intercellular transfer of exosomal wild type EGFR protein confers osimertinib resistance to EGFR-mutated sensitive Cancer cells in vitro and in vivo. Co-culture of EGFR-mutated sensitive cells and EGFR-nonmutated resistant cells promoted osimertinib resistance phenotype in EGFR-mutated Cancer cells, while depletion of exosomes from conditioned medium or blockade of exosomal EGFR by neutralizing antibody alleviated this phenotype. Mechanistically, osimertinib promoted the release of exosomes by upregulated a Rab GTPase (RAB17). Knockdown of RAB17 resulted in the decrease of exosomes secretion. Moreover, exosomes could be internalized by EGFR-mutated Cancer cells via Clathrin-dependent endocytosis and then the encapsulated exosomal wild type EGFR protein activated downstream PI3K/Akt and MAPK signaling pathways and triggered osimertinib resistance.

Conclusions: Intercellular transfer of exosomal wild type EGFR promotes osimertinib resistance in NSCLC, which may represent a novel resistant mechanism of osimertinib and provide a proof of concept for targeting exosomes to prevent and reverse the osimertinib resistance.

Keywords

Acquired resistance; Exosomes; NSCLC; Osimertinib; Wild type EGFR.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-P9905
    99.70%, EGFR Inhibitor