Photodynamic activation of a KRAS RNA G-quadruplex-targeted photosensitizer induces ferroptosis in cisplatin-resistant non-small cell lung cancer.

KRAS overactivation plays a crucial role in the development of non-small cell lung cancer (NSCLC). Although two KRAS inhibitors have been approved for NSCLC treatment, their efficacy is limited to the KRAS G12 C mutant along with the occurrence of drug resistance. Previously, we discovered a small molecule (MBD) targeting RNA G-quadruplex (RG4) in the 5'-UTR of KRAS mRNA. However, MBD exhibited some side effects, owing to the presence of KRAS RG4 in normal cells. Hence, there is a need for innovative strategies to mitigate the side effects associated with KRAS RG4-targeted ligands. In this study, we paid attention to photodynamic therapy (PDT), and thus a new photosensitizer termed MC1 was discovered. MC1 displayed considerable binding capacity and selectivity to KRAS RG4, compared to other RNAs. Photosensitivity of MC1in vitro was illustrated by KRAS RG4 breakage, GSH consumption, and NADH oxidation, leading to the occurrence of ferroptosis in cisplatin-resistant NSCLC cells. Antitumor efficacy of MC1 was verified in A549/DDP-bearing nude mice. Moreover, MC1 demonstrated superior performance than MBD in several aspects, including G4 stabilizing ability in vitro, KRAS inhibitory efficacy at the cellular level, and drug safety at the animal level. Besides, the potential of MC1 as a fluorescent probe for KRAS RG4 was characterized. To sum up, our study provides guidance for the development of KRAS RG4-targeted photodynamic therapy strategies for the treatment of NSCLC.