In summary, our analysis of protein cargo from EVs isolated from mutant EGFR‐driven NSCLC cells revealed the presence of a protein signature related to osimertinib resistance, including CSPG4, HSPG2, TAGLN, THBS1 and TNC and indicated involvement of biological pathways such as the focal adhesion and proteoglycans in cancer pathways. Here, CSPG4 is linked to cancer.