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Targeting pyruvate dehydrogenase kinase 1 overcomes EGFR C797S mutation-driven osimertinib resistance in non-small

Wonyoung Park1,2, Shibo Wei3, Chu-Long Xie4,5

  • 1Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do, 50612, Republic of Korea.

Experimental & Molecular Medicine
|April 30, 2024
PubMed

Insights

The EGFR C797S mutation causes resistance to osimertinib in non-small cell lung cancer. Pyruvate dehydrogenase kinase 1 (PDK1) drives this resistance, and inhibiting PDK1 with leelamine can overcome it.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) effective against EGFR T790M mutations in non-small cell lung cancer (NSCLC).
  • The emergence of the EGFR C797S mutation confers resistance to osimertinib, necessitating new therapeutic strategies.
  • Pyruvate dehydrogenase kinase 1 (PDK1) is implicated in various cellular processes, including cancer metabolism.

Purpose of the Study:

  • To investigate the role of PDK1 in osimertinib resistance mediated by the EGFR C797S mutation in NSCLC.
  • To explore the molecular mechanisms linking EGFR C797S, PDK1, and cancer progression.
  • To evaluate the therapeutic potential of combining osimertinib with a PDK1 inhibitor.

Main Methods:

  • Establishment of NSCLC cell lines (A549, NCI-H292, PC-9, NCI-H1975) harboring the EGFR C797S mutation for in vitro and in vivo studies.
  • Analysis of EGFR phosphorylation and downstream signaling pathways in resistant cells.
  • Assessment of PDK1 expression and its correlation with osimertinib resistance in patient samples and cell lines.
  • Evaluation of the efficacy of leelamine (PDK1 inhibitor) combined with osimertinib in allograft and xenograft models.
  • CRISPR-mediated PDK1 knockout to assess its role in tumor formation.

Main Results:

  • Elevated PDK1 expression was observed in patients with osimertinib resistance.
  • EGFR C797S mutant NSCLC cells showed increased EGFR phosphorylation and activation of downstream oncogenic pathways.
  • The EGFR C797S mutation promoted PDK1-driven glycolysis via the EGFR/AKT/HIF-1α axis.
  • Combination therapy with osimertinib and leelamine effectively overcame osimertinib resistance in vivo.
  • PDK1 knockout significantly inhibited tumor formation in xenograft models.

Conclusions:

  • The EGFR C797S mutation is linked to increased PDK1 expression and subsequent glycolysis, driving osimertinib resistance in NSCLC.
  • Targeting PDK1 represents a promising therapeutic strategy to overcome osimertinib resistance.
  • This study provides a deeper understanding of EGFR mutation-driven resistance mechanisms and opens avenues for novel targeted therapies.

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