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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
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Transfer of Damaged Mitochondria from Cancer Cells to Cancer-Associated Fibroblasts Promotes Tyrosine Kinase

Tongyan Liu1,2, Shiyi Huang3, Zhitong Li4

  • 1Department of Thoracic Surgery, Jiangsu Key Laboratory of Innovative Cancer Diagnosis & Therapeutics, Jiangsu Cancer Hospital & Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, PR China.

Cancer Research
|December 2, 2025
PubMed

Insights

Drug-tolerant persister cells promote EGFR-TKI resistance in lung cancer. Targeting cancer-associated fibroblasts via fasudil blocks mitochondrial transfer, restoring drug sensitivity and improving prognosis.

Area of Science:

  • Oncology
  • Cancer Biology
  • Cell Biology

Background:

  • Drug-tolerant persister (DTP) cells contribute significantly to therapeutic resistance in EGFR-mutant lung adenocarcinoma.
  • Identifying the mechanisms driving DTP cell survival is crucial for overcoming treatment failure.

Purpose of the Study:

  • To investigate the role of cancer-associated fibroblasts (CAFs) in sustaining DTP cells and driving resistance to EGFR tyrosine kinase inhibitors (TKIs).
  • To explore potential therapeutic strategies targeting stromal-tumor interactions to re-sensitize tumors to EGFR-TKIs.

Main Methods:

  • Single-cell RNA sequencing to identify specific CAF populations.
  • Analysis of signaling pathways (CCL11, Miro1/RhoA) involved in CAF recruitment and function.
  • Investigation of mitochondrial transfer between tumor cells and CAFs.
  • In vivo studies evaluating the efficacy of fasudil in combination with EGFR-TKI.

Main Results:

  • A distinct RGS5+MYL9+ CAF population was identified, strongly associated with EGFR-TKI resistance and poor prognosis.
  • These CAFs were recruited to DTP niches via CCL11 signaling and formed tunneling nanotubes.
  • CAFs acted as "metabolic sinks," accepting damaged mitochondria from tumor cells, thereby supporting DTP survival.
  • Fasudil treatment inhibited mitochondrial transfer and restored sensitivity to osimertinib in vivo.

Conclusions:

  • Targetable stromal-tumor crosstalk, mediated by RGS5+MYL9+ CAFs, sustains DTP populations in EGFR-mutant lung cancer.
  • Blocking Rho kinase signaling with fasudil disrupts this crosstalk and overcomes acquired resistance.
  • Combination therapy with EGFR-TKIs and Rho kinase inhibitors presents a promising strategy for treating resistant lung adenocarcinoma.

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