Cytosolic PKM2 stabilizes mutant EGFR protein expression through regulating HSP90-EGFR association

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Secondary mutations in epidermal growth factor receptor (EGFR) cause resistance to tyrosine kinase inhibitors (TKIs), a major challenge in lung cancer treatment.
• Developing strategies to overcome TKI resistance is crucial for improving patient outcomes in lung cancer therapy.

Purpose of the Study:

• To investigate the role of pyruvate kinase M2 (PKM2) in acquired resistance to EGFR-TKIs in lung cancer.
• To elucidate the mechanism by which PKM2 contributes to EGFR stabilization and signaling.

Main Methods:

• PKM2 silencing in TKI-sensitive and -resistant lung cancer cell lines and xenografts.
• Analysis of mutant EGFR expression, EGFR-related signaling pathways, and protein-protein interactions.
• Investigation of PKM2's oligomeric state (dimer vs. tetramer) and its effect on EGFR stability.

Main Results:

• PKM2 directly interacts with mutant EGFR and heat-shock protein 90 (HSP90), stabilizing EGFR and sustaining cell survival signaling.
• PKM2 silencing significantly reduced mutant EGFR expression, inhibited tumor growth in vivo, and downregulated EGFR signaling.
• EGFR stabilization by PKM2 depends on its dimeric form; PKM2 tetramerization decreased mutant EGFR half-life.
• Clinical PKM2 levels correlated positively with mutant EGFR expression and patient outcomes.

Conclusions:

• PKM2 has a non-glycolytic cytoplasmic function that stabilizes mutant EGFR, contributing to EGFR-dependent lung tumorigenesis.
• Targeting PKM2 represents a novel therapeutic strategy to overcome resistance to EGFR-TKIs in lung cancer.