2022 World Conference on Lung Cancer (ePosters)-EP08.02-055. Targeting Lung Adenocarcinoma Cells with a Novel Disulfide Reductase Inhibitor

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In a recent study, researchers aimed to develop more effective therapies for lung cancer, the leading cause of cancer-related deaths worldwide. The main oncogenic drivers of lung cancer are KRAS and EGFR, which are part of the MAPK signaling pathway. Targeted therapies that inhibit this pathway often lead to drug resistance, highlighting the need for alternative treatments. The researchers conducted a high-throughput screen to identify compounds that selectively inhibit the growth of lung cancer cells with mutations in KRAS and EGFR. One of the compounds, called LCS3, showed promising specificity for inhibiting lung cancer proliferation but its mechanism of action was unknown. The researchers screened 27 lung cancer cell lines and found that most of them were sensitive to LCS3. The project aimed to identify the specific molecular target of LCS3 and its broader mechanism of action. The researchers used thermal proteome profiling to identify proteins that interact with LCS3 and found that it targets enzymes involved in redox homeostasis. They validated the inhibition of these enzymes, GSR and TXNRD1, in the lab and showed that LCS3 depletes cells of reduced glutathione and induces oxidative stress. Furthermore, they found that NQO1, another enzyme involved in redox homeostasis, is essential for LCS3-induced cell toxicity. The researchers also performed a CRISPR-Cas9 knockout screen and identified NQO1 suppression as a mechanism of resistance to LCS3. These findings provide insights into the mechanisms underlying the sensitivity of lung cancer cells to LCS3 and could potentially lead to the development of novel therapeutic targets and strategies to overcome drug resistance in lung cancer.

Asset Subtitle

Fraser Johnson

Meta Tag

Speaker Fraser Johnson

Topic Metastatic Non-small Cell Lung Cancer - Molecular Targeted Treatments

Keywords

lung cancer

therapies

KRAS

EGFR

MAPK signaling pathway

drug resistance

LCS3

redox homeostasis

NQO1

novel therapeutic targets