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• W4385156670 abstract "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, cancer cells frequently develop additional alterations that sustain their proliferation capacity. This acquired resistance represents a substantial hurdle in precision medicine for patients with lung cancer. Methods The biological and cellular properties of the G-quadruplex ligand BMVC-8C3O and its anticancer activities were evaluated in non-small cell lung carcinomas. In addition, combined treatment with BMVC-8C3O and osimertinib was evaluated for its effects on the growth of osimertinib-resistant tumors in vivo. Results We demonstrate that BMVC-8C3O effectively suppresses c-FOS expression by stabilizing G-rich sequences located at the c-FOS promoter. The suppression c-FOS expression by BMVC-8C3O increases the sensitivity of acquired resistant cancer cells to osimertinib. Combining BMVC-8C3O and osimertinib has a synergistic effect in inhibiting the growth of acquired resistant cancers both in vitro and in mouse models. The combined inhibitory effect is not limited to BMVC-8C3O, either: several G-quadruplex ligands show varying levels of inhibition activity. We also show that simultaneous inhibition of both the c-FOS and PI3K/AKT pathways by BMVC-8C3O and osimertinib synergistically inhibits the growth of acquired resistant cancer cells. Conclusion These findings unveil a synthetic lethal strategy to prevent and inhibit epidermal growth factor receptor–altered lung cancers with acquired osimertinib resistance. G-quadruplex ligands have the potential to be integrated into current osimertinib-based treatment regimens." @default.
• W4385156670 created "2023-07-24" @default.
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• W4385156670 date "2023-07-22" @default.
• W4385156670 modified "2023-10-18" @default.
• W4385156670 title "Suppressing <i>c-FOS</i> expression by G-quadruplex ligands inhibits osimertinib-resistant non-small cell lung cancers" @default.
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• W4385156670 doi "https://doi.org/10.1093/jnci/djad142" @default.
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