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Dapk2 dysfunction leads to Mic60 lactylation and mitochondrial metabolic reprogramming, promoting lung cancer

Jie Zheng1, Han She2, Rui Han3

  • 1Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing 400042, China; School of Medicine, Chongqing University, Chongqing 400044, China.

Developmental Cell
|August 14, 2025
PubMed

Insights

Mitochondrial changes drive epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance and lung cancer metastasis. Targeting these mitochondrial alterations may overcome resistance and inhibit cancer spread.

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolism

Background:

  • Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance is a major challenge in lung cancer treatment.
  • Tumor metastasis is a significant cause of mortality in EGFR-TKI-resistant lung cancer.
  • Controlling metastasis is crucial for improving patient outcomes.

Purpose of the Study:

  • To identify key mechanisms driving EGFR-TKI resistance and lung cancer metastasis.
  • To investigate the role of mitochondrial dynamics and metabolism in cancer progression.
  • To explore potential therapeutic targets for overcoming EGFR-TKI resistance and metastasis.

Main Methods:

  • Utilized an anoikis-resistant cell model to study resistance mechanisms.
  • Employed a mouse tail vein metastasis model to assess metastatic potential.
  • Analyzed mitochondrial cristae remodeling and metabolic reprogramming in EGFR-TKI-resistant cells.
  • Investigated the function of death-associated protein kinase 2 (Dapk2) and Mic60 protein.

Main Results:

  • EGFR-TKI-resistant cells showed enhanced anoikis resistance (AR) and mitochondrial metabolism.
  • These resistant cells exhibited a higher propensity for metastasis.
  • Dapk2 dysfunction altered Mic60, leading to increased mitochondrial cristae abundance and compactness.
  • This restructuring activated mitochondrial metabolism, potentially via Mic60 lactylation.

Conclusions:

  • Mitochondrial cristae remodeling and metabolic reprogramming are critical hubs for EGFR-TKI resistance and metastasis.
  • Dapk2-mediated alterations in Mic60 and mitochondrial morphology play a key role.
  • Mic60 lactylation may be a crucial mechanism linking mitochondrial changes to metabolic activation.
  • These findings offer potential therapeutic strategies to combat EGFR-TKI resistance and lung cancer metastasis.
Keywords:
EGFR-TKI resistanceNSCLClactylationmetastasismitochondrial metabolism

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