Proteogenomics: finding targets for never-smoker lung cancer

Researchers have utilised multi-omics analysis to elucidate the overexpression of oestrogen signalling pathways in specific Korean never-smoking lung cancer cases, and suggested that saracatinib, the anti-cancer drug, could be a targeted therapeutic agent. The study was conducted by the Chemical Life Convergence Research Center at the Korea Institute of Science and Technology (KIST), Korea Research Institute of Bioscience and Biotechnology, and the National Cancer Center.

Although the primary cause of lung cancer is smoking, the incidence of lung cancer among never-smokers has been increasing, particularly among women. Approximately 80 percent of never-smoking lung cancer patients are prescribed targeted therapies that focus on mutations in proteins like EGFR and ALK, but the remaining patients often receive cytotoxic chemotherapy with undesirable side effects and low response rates.

The researchers obtained tissue samples from 101 Korean never-smoking lung cancer patients without identified treatment targets from 1,597 patients who visited the National Cancer Center over the past decade. The clinical data, as well as genomic, transcriptomic, proteomic, and phosphoproteomic data, was distributed to each omics analysis method for mutual referencing. Proteomic analysis measured an average of over 9,000 proteins and 5,000 phosphorylated proteins per sample using only 100 μg of protein. This is 10 percent of the amount required for conventional protein analysis, using isotopic labelling techniques.

Driver mutations of genes associated with cancer, like STK11 and ERBB2, were found in tissues of never-smoking lung cancer patients by analysis of genetic mutations and cellular signalling pathways. Also, while the oestrogen signalling pathway was found to be overexpressed, there were no significant changes in oestrogen hormone receptors. A sub oestrogen signalling transduction protein inhibitor named saracatinib, demonstrated statistically significant (p<0.01) cell death effects when applied to cells with mutations in STK11 and ERBB2 compared to the control group without these mutations.

Moving forwards, the team is developing a molecular diagnostic technique for identifying patients with specific expression of oestrogen signalling pathways among never-smoking lung cancer patients. Furthermore, in collaboration with the National Cancer Center, they intend to conduct preclinical trials of saracatinib’s therapeutic effects on never-smoking lung cancer animal models.

Dr Lee Cheolju of KIST concluded:  “This successful case of discovering new therapeutic targets for refractory cancer through multi-omics analysis is based on purely domestic research and the collaborative efforts of hospitals and research institutions, which holds significant meaning. Building on this experience, we will lead the expansion of multi-omics research on human diseases.”

This study was published in Cancer Research.