Nanoparticles targeting mutant p53 overcome chemoresistance and tumor recurrence in non-small cell lung cancer

Yu-Yang Bi, Qiu Chen, Ming-Yuan Yang, Lei Xing and Hu-Lin Jiang ()
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Yu-Yang Bi: China Pharmaceutical University
Qiu Chen: China Pharmaceutical University
Ming-Yuan Yang: China Pharmaceutical University
Lei Xing: China Pharmaceutical University
Hu-Lin Jiang: China Pharmaceutical University

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Non-small cell lung cancer (NSCLC) shows high drug resistance and leads to low survival due to the high level of mutated Tumor Protein p53 (TP53). Cisplatin is a first-line treatment option for NSCLC, and the p53 mutation is a major factor in chemoresistance. We demonstrate that cisplatin chemotherapy increases the risk of TP53 mutations, further contributing to cisplatin resistance. Encouragingly, we find that the combination of cisplatin and fluvastatin can alleviate this problem. Therefore, we synthesize Fluplatin, a prodrug consisting of cisplatin and fluvastatin. Then, Fluplatin self-assembles and is further encapsulated with poly-(ethylene glycol)–phosphoethanolamine (PEG–PE), we obtain Fluplatin@PEG–PE nanoparticles (FP NPs). FP NPs can degrade mutant p53 (mutp53) and efficiently trigger endoplasmic reticulum stress (ERS). In this study, we show that FP NPs relieve the inhibition of cisplatin chemotherapy caused by mutp53, exhibiting highly effective tumor suppression and improving the poor NSCLC prognosis.

Date: 2024
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DOI: 10.1038/s41467-024-47080-3

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