Endostar overcomes Osimertinib-resistance mediated EGFR-activation mutation, T790M and cis-C797S triple mutations via enhancing the binding of Osimertinib to EGFR protein.

[AIMS] The EGFR-C797S mutation is the main cause of Osimertinib resistance. No effective treatment regimen is currently available for patients harboring EGFR-activation mutation/T790M/cis-C797S triple mutations.

[MATERIALS AND METHODS] Nine patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR-activation mutation/T790M/cis-C797S mutation were investigated. After Osimertinib resistance, these patients were treated with Endostar combination with Osimertinib. Network pharmacology and molecular dynamics simulations were used to clarify active sites of Endostar and the effect on protein conformation. In vivo and in vitro, EGFR L858R-T790M-C797S/H1975 cells were used to investigate the efficacy of co-treatment.

[KEY FINDINGS] Two patients achieved partial response (PR), six achieved stable disease (SD) and one had progressive disease (PD) at the 6-month efficacy assessment of co-treatment, resulting in an objective response rate (ORR) of 66.7% and a disease control rate (DCR) of 88.9%. These patients achieved a median progression-free survival (PFS) of 8.9 months and a median overall survival (OS) of 18.5 months, and no patients experienced grade III or IV adverse events. Endostatin, the active ingredient of Endostar, bound EGFR to "pseudo" mediate EGFR signaling pathway, and the introduction of Endostar enhanced the binding of Osimertinib to EGFR L858R/T790M/C797S protein. In vitro and in vivo experiments have found the co-treatment restored sensitivity to Osimertinib. Moreover, the combination therapy significantly inhibited the activation of the EGFR signaling pathway and tumor neovascularization.

[SIGNIFICANCE] This work demonstrated for the first time that Endostar enhanced the antitumor efficacy of Osimertinib, offering a potential therapeutic approach for patients harboring triple mutations.