2024 Asia Conference on Lung Cancer (ACLC) - Poster & ePosters-PP01.16

PP01.16 - Nan Jiang

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This study investigates the role of RRM1 inhibition in enhancing the effectiveness of DNA hypomethylating agents (DNMTi), specifically decitabine (DAC), for the treatment of lung adenocarcinoma. Although DNA methylation is associated with tumor development, hypomethylating agents have not been clinically effective in solid tumors like lung cancer. The primary challenge is the inadequate incorporation of these agents into tumor cell DNA.<br /><br />The research shows that inhibiting ribonucleotide reductase M1 (RRM1) increases DAC integration into the genomic DNA of lung adenocarcinoma cells. Experimentation on the A549 lung adenocarcinoma cell line and a variety of other tumor cell lines demonstrated that RRM1 inhibition leads to a higher rate of DAC incorporation. Through a series of laboratory techniques such as Western blotting and LC-MS/MS, it was shown that RRM1 knockdown enhances the sensitivity of cells to DAC treatment, reflected in both increased DAC incorporation and reduced IC50 values. Additionally, the study reveals that RRM1 inhibition results in increased expression of tumor suppressor genes like RASSF1A.<br /><br />Further experiments in mouse models support this finding. In xenograft models using lung adenocarcinoma cells, RRM1 knockdown combined with DAC treatment resulted in significant tumor volume reduction compared to DAC treatment alone. The study also identifies a potential combination therapy involving RNR inhibitors like 3-AP with DAC, which collaboratively suppresses tumor growth.<br /><br />Concluding, the research pinpoints RRM1 overexpression as a barrier to effective DAC therapy in lung adenocarcinoma and suggests that combining DNA hypomethylating agents with RNR inhibitors can be a promising therapeutic strategy, providing a potentially improved treatment regimen for lung cancer patients.

Keywords

RRM1 inhibition

DNA hypomethylating agents

decitabine

lung adenocarcinoma

tumor cell DNA

A549 cell line

Western blotting

tumor suppressor genes

xenograft models

combination therapy