TP53 transcription factor for the NEDD9/HEF1/Cas-L gene: potential targets in Non-Small Cell Lung Cancer treatment
Bénédicte Rousseau1, Catherine Jacquot1, Julie Le Palabe1
1IICiMED/EA 1155 - Département Cancer du Poumon et Cibles Moléculaires, UFR Sciences Pharmaceutiques - 9 rue Bias - BP53508 - 44035 NANTES CEDEX 1 - FRANCE.
Abstract:
Lung cancer is a serious public health problem. Although there has been significant progress in chemotherapy, non-small cell lung cancer is still resistant to current treatments, primarily because of the slow rate of cell development. It is thus important to find new molecules directed against targets other than proliferation agents. Considering the high proportion of mutant proteins in tumor cells, and the high rate of mutation of the TP53 gene in all cancers, and in NSCLC in particular, this gene is a perfect target. Certain new molecules have been shown to restore the activity of mutated p53 protein, for example PRIMA-1, which reactivates the His273 mutant p53. In a previous study, we presented triazine A190, a molecule with a cytostatic activity that blocks cells in the G1 phase and induces apoptosis. Here, we show that A190 not only restores mutant p53 activity, but also induces an overexpression of the NEDD9 gene, leading to apoptotic death. These findings might offer hope for the development of new targeted therapies, specific to tumor cells, which spare healthy cells.
Insights
New triazine A190 molecule shows promise for non-small cell lung cancer (NSCLC) treatment. It restores mutant p53 activity and overexpresses NEDD9, leading to tumor cell death and offering hope for targeted therapies.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Non-small cell lung cancer (NSCLC) presents a significant public health challenge, exhibiting resistance to conventional chemotherapy due to slow cell development.
- The TP53 gene is frequently mutated in NSCLC, making mutated p53 a critical therapeutic target.
- Existing treatments often focus on proliferation, necessitating novel approaches targeting alternative pathways.
Purpose of the Study:
- To investigate the therapeutic potential of triazine A190 in NSCLC.
- To elucidate the molecular mechanisms underlying A190's anti-cancer effects.
- To explore A190's impact on mutant p53 activity and gene expression.
Main Methods:
- Cell-based assays to assess cytostatic and apoptotic effects.
- Analysis of p53 protein activity restoration.
- Gene expression profiling to identify downstream targets, specifically NEDD9.
- In vitro studies using NSCLC models.
Main Results:
- Triazine A190 demonstrates cytostatic activity, arresting cells in the G1 phase and inducing apoptosis.
- A190 effectively restores the activity of mutant p53 protein.
- A190 significantly induces overexpression of the NEDD9 gene, contributing to apoptotic cell death.
- The molecule exhibits specificity towards tumor cells.
Conclusions:
- Triazine A190 represents a promising candidate for novel NSCLC targeted therapies.
- Restoration of mutant p53 activity and NEDD9 overexpression are key mechanisms of A190's efficacy.
- These findings pave the way for developing tumor-specific treatments that spare healthy cells.
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