Genetic modulation of ABCB1: Sunvozertinib reverses ABCB1-mediated multidrug resistance in cancer cells.

Sunvozertinib is an oral, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) designed to treat non-small cell lung cancer (NSCLC) patients with EGFR exon 20 insertion mutations under a phase II clinical trial. In this study, we investigated whether sunvozertinib could antagonize ABCB1, also known as multidrug resistance 1 (MDR1/P-gp). ABCB1 is a gene that encodes an important drug transport protein that pumps various substances, including drugs and toxins, out of cells. Sunvozertinib received a high score in docking analysis, indicating a strong interaction between sunvozertinib and ABCB1. ATPase assay indicated that sunvozertinib stimulated ABCB1 ATPase activity in a concentration-dependent manner. MTT assay shows that sunvozertinib significantly reversed ABCB1-mediated MDR but not ABCC1- and ABCG2-mediated MDR. Mechanistic studies show that sunvozertinib significantly reversed ABCB1-mediated MDR by attenuating the efflux activity of the ABCB1 transporter. Furthermore, treatment with sunvozertinib did not change protein expression or subcellular localization of ABCB1. Altogether, these data demonstrate that sunvozertinib, when combined with other conventional chemotherapeutic agents, can overcome MDR and improve therapeutic effect.