An intrinsic purine metabolite AICAR blocks lung tumour growth by targeting oncoprotein mucin 1

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Lung cancer frequently overexpresses mucin 1 (MUC1) and its active subunit MUC1-CT.
• While peptides targeting MUC1 exist, MUC1-targeting metabolites are less explored.
• AICAR (5-aminoimidazole-4-carboxamide ribonucleotide) is an intermediate in purine biosynthesis.

Purpose of the Study:

• To investigate the effect of AICAR on lung cancer cells, particularly those with EGFR mutations.
• To determine if AICAR can target MUC1 and its associated signaling pathways.
• To evaluate AICAR's potential as a therapeutic agent for lung cancer.

Main Methods:

• Assessed cell viability and apoptosis in AICAR-treated lung cancer cells (EGFR-mutant and wild-type).
• Identified AICAR-binding proteins using in silico and thermal stability assays.
• Analyzed MUC1 expression and AICAR's impact on protein-protein interactions (MUC1-CT, JAK1, EGFR) via RNA sequencing and imaging techniques.
• Evaluated AICAR's efficacy alone and in combination with JAK and EGFR inhibitors in patient-derived and mouse models.

Main Results:

• AICAR reduced EGFR-mutant lung cancer cell growth by inducing DNA damage and apoptosis.
• MUC1 was identified as a key AICAR-binding and degrading protein.
• AICAR negatively regulated JAK signaling and the JAK1-MUC1-CT interaction.
• Combined treatment with AICAR and JAK/EGFR inhibitors significantly reduced tumor organoid growth.

Conclusions:

• AICAR effectively represses MUC1 activity in EGFR-mutant lung cancer.
• AICAR disrupts critical protein-protein interactions involving MUC1-CT, JAK1, and EGFR.
• AICAR demonstrates therapeutic potential for EGFR-mutant lung cancer, particularly when combined with JAK and EGFR inhibitors.