Advancing Precision Medicine by Integrating Genomic, Transcriptomic, Proteomic, and Clinical Data

While smoking remains the leading cause of lung cancer, a rising number of cases in non-smokers—particularly among women—has been documented. Roughly 80% of lung cancer patients who never smoked receive treatments targeting specific protein mutations, like those in the EGFR and ALK genes. For those without such mutations, however, treatment often involves chemotherapy, which typically produces lower response rates and harsher side effects, emphasizing the need to develop more effective targeted therapies.

A collaborative research team led by Dr. Lee Cheolju at the Chemical Life Convergence Research Center, Korea Institute of Science and Technology (KIST), in partnership with Dr. Kim Seon-Young's group at the Korea Research Institute of Bioscience and Biotechnology, and Dr. Han Ji-Youn's team at the National Cancer Center, has utilized multi-omics analysis to shed light on overexpression of estrogen signaling pathways in certain Korean non-smoking lung cancer cases. The team also identified saracatinib as a promising targeted drug. The multi-omics approach allows for the integration of various layers of molecular data, with proteomics posing a specific challenge due to the necessity of evaluating minuscule protein quantities—often in microgram amounts—without loss.

Collecting samples from 101 non-smoking lung cancer patients without detectable therapeutic targets from a pool of 1,597 cases within the National Cancer Center’s records over the last decade, the researchers employed a variety of omics techniques—genomic, transcriptomic, proteomic, and phosphoproteomic analyses. Significantly, proteomics analysis recorded an average measurement of over 9,000 proteins and 5,000 phosphorylated proteins per sample, all derived from just 100 μg of protein, a tenth of the usual sample requirement, using advanced isotopic labeling methods.

Through the multi-omics lens, the team discovered mutations in cancer-linked genes like STK11 and ERBB2 within these non-smoker patient samples. They also observed heightened activity in estrogen signaling pathways, though there were no notable changes in the estrogen hormone receptors themselves. Consequently, it was discovered that saracatinib, a drug that targets estrogen pathway signaling proteins, markedly increased cell death (p<0.01) in cells with STK11 and ERBB2 mutations compared to unaffected controls.

Building on these findings, the researchers are now working on a molecular diagnostic tool aimed at detecting lung cancer patients exhibiting specific estrogen pathway activity. Additionally, preclinical trials are planned in collaboration with the National Cancer Center to test the efficacy of saracatinib treatment in animal models of non-smoker lung cancer.

Dr. Lee Cheolju highlighted the significance of this research, stating, "This discovery of new therapeutic targets for difficult-to-treat cancers showcases the potential of multi-omics analysis. It’s a milestone achieved through domestic resources and collaboration between hospitals and research centers. Using this as a foundation, we will continue pushing the frontiers of multi-omics research to tackle a broader range of human diseases."

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KIST, established in 1966 as Korea's first government-funded research institute, is focused on solving national and social issues while driving innovation in scientific research. For more details, visit KIST’s website at https://eng.kist.re.kr/.

This research was funded by Korea's Ministry of Science and ICT, under KIST’s major projects and the Bio-Medical Technology Development Program (2022M3H9A2096187). The detailed results of the study were published in the latest edition of Cancer Research (Impact Factor 11.2, JCR field ranking 10.6%).

Journal

Cancer Research

DOI

10.1158/0008-5472.CAN-23-1551

Article Title

Proteogenomic Characterization Reveals Estrogen Signaling as a Target for Never-Smoker Lung Adenocarcinoma Patients without EGFR or ALK Alterations

Article Publication Date

15-Apr-2024