Suppressing c-FOS expression by G-quadruplex ligands inhibits osimertinib-resistant non-small cell lung cancers
Menée in vitro et sur des souris, cette étude met en évidence un mécanisme par lequel le ligand G-quadruplex BMVC-8C3O, en supprimant l'expression de c-FOS, inhibe la résistance à l'osimertinib des carcinomes pulmonaires non à petites cellules
Osimertinib stands as the first-line therapy for patients with non-small cell lung cancers harboring epidermal growth factor receptor (EGFR) mutations. Although osimertinib has been shown to elicit profound patient responses, cancer cells frequently develop additional mutations that sustain their proliferation capacity. This acquired resistance represents a significant hurdle in precision medicine for lung cancer patients.The biological and cellular properties of a G-quadruplex (G4) ligand BMVC-8C3O, as well as its anti-cancer activities, were evaluated in non-small cell lung carcinomas (NSCLCs). Additionally, the combined treatment of BMVC-8C3O and osimertinib was evaluated for its effects on the growth of osimertinib-resistant tumors in vivo.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 animal models. The combined inhibitory effect is not limited to BMVC-8C3O, as several G4 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.These findings unveil a synthetic lethal strategy to prevent and to inhibit EGFR-mutated lung cancers with acquired osimertinib-resistance. G4 ligands have the potential to be integrated into current osimertinib-based treatment regimens.