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Genome-scale CRISPR-Cas9 screen identifies PAICS as a therapeutic target for EGFR wild-type non-small cell lung
Yufeng Li1,2, Lingyun Zhu3, Jiaqi Mao3
1Department of Medical Oncology The First Affiliated Hospital of Nanjing Medical University Nanjing Jiangsu China.
Abstract:
Epidermal growth factor receptor-targeted (EGFR-targeted) therapies show promise for non-small cell lung cancer (NSCLC), but they are ineffective in a third of patients who lack EGFR mutations. This underlines the need for personalized treatments for patients with EGFR wild-type NSCLC. A genome-wide CRISPR/Cas9 screen has identified the enzyme phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), which is vital in de novo purine biosynthesis and tumor development, as a potential drug target for EGFR wild-type NSCLC. We have further confirmed that PAICS expression is significantly increased in NSCLC tissues and correlates with poor patient prognosis. Knockdown of PAICS resulted in a marked reduction in both in vitro and in vivo proliferation of EGFR wild-type NSCLC cells. Additionally, PAICS silencing led to cell-cycle arrest in these cells, with genes involved in the cell cycle pathway being differentially expressed. Consistently, an increase in cell proliferation ability and colony number was observed in cells with upregulated PAICS in EGFR wild-type NSCLC. PAICS silencing also caused DNA damage and cell-cycle arrest by interacting with DNA repair genes. Moreover, decreased IMPDH2 activity and activated PI3K-AKT signaling were observed in NSCLC cells with EGFR mutations, which may compromise the effectiveness of PAICS knockdown. Therefore, PAICS plays an oncogenic role in EGFR wild-type NSCLC and represents a potential therapeutic target for this disease.
Insights
Phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) is a promising drug target for EGFR wild-type non-small cell lung cancer. Targeting PAICS inhibits tumor growth and causes cell-cycle arrest, offering new therapeutic avenues.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Epidermal growth factor receptor (EGFR)-targeted therapies are effective for non-small cell lung cancer (NSCLC) but fail in patients without EGFR mutations.
- There is a critical need for personalized treatment strategies for EGFR wild-type NSCLC.
- Identifying novel molecular targets is essential for advancing treatment efficacy in NSCLC.
Purpose of the Study:
- To identify and validate potential therapeutic targets for EGFR wild-type NSCLC.
- To investigate the role of phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) in NSCLC pathogenesis.
- To evaluate PAICS as a potential drug target for EGFR wild-type NSCLC.
Main Methods:
- Genome-wide CRISPR/Cas9 screening to identify potential drug targets.
- Analysis of PAICS expression in NSCLC tissues and correlation with patient prognosis.
- In vitro and in vivo studies involving PAICS knockdown and upregulation in NSCLC cells.
- Cell-cycle analysis and DNA damage assessment.
- Investigation of signaling pathways including IMPDH2 and PI3K-AKT.
Main Results:
- PAICS was identified as a crucial enzyme in de novo purine biosynthesis and tumor development.
- PAICS expression is significantly elevated in NSCLC tissues and associated with poor prognosis.
- PAICS knockdown markedly reduced proliferation and induced cell-cycle arrest in EGFR wild-type NSCLC cells.
- PAICS silencing led to DNA damage and altered expression of cell cycle and DNA repair genes.
- Upregulation of PAICS increased proliferation and colony formation in EGFR wild-type NSCLC.
- EGFR mutations were associated with decreased IMPDH2 activity and activated PI3K-AKT signaling, potentially impacting PAICS knockdown efficacy.
Conclusions:
- PAICS plays a significant oncogenic role in EGFR wild-type NSCLC.
- PAICS represents a promising and specific therapeutic target for EGFR wild-type NSCLC.
- Targeting PAICS offers a potential strategy to overcome treatment resistance in a subset of NSCLC patients.
