Abstract 1839: Nanobodies against EGF enhance the antitumoral effect of osimertinib and overcome resistance in non-small cell lung cancer cell models

Abstract

Abstract Background: The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) osimertinib improves therapy for non-small cell lung cancer (NSCLC) patients who possess EGFR mutations. However, acquired resistance appears invariably due to several mechanisms. The strategy of using EGF-targeted nanobodies (Nbs) to block the initial step of the EGFR pathway constitutes a new research area. Nbs also offer several advantages compared to traditional mAbs, such as their reduced size, higher stability and tissue penetration, low production costs and lack of Fc effector function, which provide key advantages for targeting soluble tumoral growth factors. In this study we investigated the efficacy of anti-EGF Nbs to reduce osimertinib-resistance. Experimental procedures: Cell viability and colony formation assays were performed in PC9 and PC9-osimertinib-resistant NSCLC cell lines tested with anti-EGF Nbs alone or in combination with osimertinib. To analyze the mechanism of action of these compounds and its combination, western blot analysis was carried out to study protein expression and activation. Summary of data: Two anti-EGF Nbs, generated in our laboratory, inhibited cell viability and colony formation in PC9 and PC9-derived osimertinib-resistant cell lines. The combination of these Nbs with osimertinib improved the antitumoral efficacy of this EGFR-TKI in cell viability and colony formation experiments. The combination of anti-EGF Nbs with osimertinib clearly decreases the activation of proteins involved in the EGFR pathway, such as, EGFR, Akt and Erk 1/2. In addition, it increases cellular apoptosis, and decreases the expression of Hes1, a marker of cancer stem cells involved in metastasis and osimertinib resistance mechanisms. Conclusions: We conclude that the combination of anti-EGF nanobodies and osimertinib exhibits a good efficacy in inhibiting cell viability and colony formation, while, inhibiting expression and activation of proteins involved in osimertinib resistance. Citation Format: Salvador Guardiola, Macarena Sánchez-Navarro, Ernest Giralt, Rafael Rosell, Jordi Codony-Servat. Nanobodies against EGF enhance the antitumoral effect of osimertinib and overcome resistance in non-small cell lung cancer cell models [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 1839.