NDRG1 expression in cancers confers dependence on DNA damage repair and sensitivity to quinacrine

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Cancer cells utilize DNA repair mechanisms to survive.
• Targeting DNA repair pathways presents a therapeutic strategy for cancer treatment.
• Tumor cells with deficiencies in one repair pathway may be vulnerable to inhibition of others.

Purpose of the Study:

• To investigate the effect of the antimalarial drug quinacrine on the DNA damage response (DDR) in cancer cells.
• To identify the molecular mechanisms by which quinacrine affects DDR.
• To explore potential therapeutic strategies based on quinacrine's activity and cancer-specific vulnerabilities.

Main Methods:

• In silico analysis.
• High-content genetic screening.
• Cell survival assays.
• Protein interaction studies.
• Ubiquitin ligase degradation analysis.
• DNA damage marker assessment.
• Correlation analysis of gene expression with patient survival and drug sensitivity.

Main Results:

• Quinacrine impairs the DDR in various cancer cell lines by disrupting the NDRG1-VCP interaction.
• This disruption leads to RNF8 degradation and impaired recruitment of 53BP1 to DNA damage sites, evidenced by increased γH2AX.
• High NDRG1 expression correlates with poor patient survival and quinacrine sensitivity.
• Colorectal cancer cells exhibit synthetic lethality upon NDRG1 inhibition combined with MLH1 or PARP3 mutations.

Conclusions:

• Quinacrine targets the DNA damage response by interfering with key protein interactions.
• NDRG1 expression levels can predict quinacrine sensitivity and patient prognosis.
• Combination therapies targeting NDRG1, MLH1, and PARP3 show promise for colon cancer treatment.