AURKB as a target in non-small cell lung cancer with acquired resistance to anti-EGFR therapy

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Non-small cell lung cancer (NSCLC) frequently develops resistance to EGFR tyrosine kinase inhibitors (EGFR TKIs).
• Mechanisms of resistance, particularly in the absence of known mutations like p.T790M, require further investigation.
• Identifying alternative therapeutic targets is crucial for improving outcomes in resistant NSCLC.

Purpose of the Study:

• To investigate the role of Aurora B kinase (AURKB) in acquired resistance to EGFR TKIs in NSCLC.
• To evaluate the efficacy of AURKB inhibitors in preclinical models of EGFR TKI-resistant NSCLC.
• To explore AURKB activity as a potential biomarker for resistance and survival in NSCLC patients.

Main Methods:

• Treatment of EGFR TKI-resistant NSCLC cell lines with AURKB inhibitors (barasertib, S49076).
• Assessment of phospho-histone H3 (pH3) levels, cell cycle progression (G1/S arrest), polyploidy, and cell death.
• Analysis of pH3 levels and correlation with survival in NSCLC patient samples post-EGFR TKI progression.

Main Results:

• Resistant NSCLC cells lacking acquired mutations were sensitive to AURKB inhibitors.
• AURKB inhibition reduced pH3 levels, induced G1/S arrest, and caused polyploidy.
• Polyploidy led to cell death in the absence of acquired mutations, and senescence in their presence.
• Increased pH3 levels were observed in NSCLC patients after progression on EGFR TKIs, with high baseline pH3 correlating with shorter survival.

Conclusions:

• AURKB activation is linked to acquired resistance to EGFR TKIs in NSCLC.
• AURKB inhibitors represent a potential therapeutic strategy for NSCLC progressing on anti-EGFR therapy, especially in tumors without resistance mutations.
• AURKB activity serves as a biomarker for resistance and prognosis in EGFR TKI-treated NSCLC patients.