Suppressing c-FOS expression by G-quadruplex ligands inhibits osimertinib-resistant non-small cell lung cancer

• DOI: 10.1093/jnci/djad142
• Publication Date: 2023-07-23T10:06:46Z
• Authors: Kai Lu; Hsin-Chiao Wang; Yi-Chen Tu; Cheng-Chung Chang; Pei-Jen Lou; Ta-Chau Chang; Jing-Jer Lin
• Keywords: Osimertinib; Growth inhibition

Abstract Background Osimertinib is the first-line therapy for patients with non-small cell lung cancer harboring epidermal growth factor receptor–activating alterations. Although osimertinib has been shown to elicit profound patient responses, cells frequently develop additional alterations that sustain their proliferation capacity. This acquired resistance represents a substantial hurdle in precision medicine cancer. Methods The biological and cellular properties of G-quadruplex ligand BMVC-8C3O its anticancer activities were evaluated carcinomas. In addition, combined treatment was effects on osimertinib-resistant tumors vivo. Results We demonstrate effectively suppresses c-FOS expression by stabilizing G-rich sequences located at promoter. suppression increases sensitivity resistant osimertinib. Combining synergistic effect inhibiting cancers both vitro mouse models. inhibitory not limited BMVC-8C3O, either: several ligands show varying levels inhibition activity. also simultaneous PI3K/AKT pathways synergistically inhibits cells. Conclusion These findings unveil synthetic lethal strategy prevent inhibit receptor–altered resistance. have potential be integrated into current osimertinib-based regimens.