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Updated: Apr 16, 2026

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Therapy-induced cholesterol biosynthesis drives lung cancer dormancy and drug resistance

Yikai Zhao1, Yijia Zhou2, Linnuo Pan1

  • 1Key Laboratory of Multi-Cell Systems, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.

The Journal of Clinical Investigation
|April 15, 2026
PubMed

Insights

Lung cancer targeted therapies can induce dormancy by boosting cholesterol synthesis. Combining statins and aurora kinase inhibitors with targeted drugs dramatically improved tumor regression and prevented drug resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Molecular targeted therapies for lung cancer (EGFR, KRAS, ALK) show clinical success but rarely achieve complete response.
  • Cancer cells can enter a dormant state to evade drug-induced cell death, contributing to treatment resistance.

Purpose of the Study:

  • To investigate the mechanisms by which lung cancer cells enter dormancy during targeted therapy.
  • To identify novel therapeutic strategies to overcome drug resistance and enhance treatment efficacy in lung cancer.

Main Methods:

  • Analysis of molecular pathways involved in therapy-induced dormancy in EGFR, KRAS, and ALK-mutant lung cancer models.
  • Assessment of cholesterol biosynthesis inhibitors (statins) and aurora kinase inhibitors in combination with targeted therapies.
  • Evaluation of the unfolded protein response (UPR) and PERK-eIF2α signaling in cancer dormancy.

Main Results:

  • Targeted therapy induced cholesterol biosynthesis, promoting cancer cell dormancy and drug resistance.
  • Combined statin treatment blocked cholesterol biosynthesis, prevented dormancy, and led to significant tumor regression.
  • A subpopulation of sensitive cycling cancer cells was identified, responsive to aurora kinase inhibitors.
  • Triple targeting of cholesterol biosynthesis, aurora kinase, and oncogenic drivers resulted in near-complete tumor eradication.

Conclusions:

  • Therapy-induced activation of the UPR, particularly the PERK-eIF2α axis, drives cholesterol biosynthesis and AKT signaling, promoting cancer dormancy.
  • Combining cholesterol biosynthesis inhibition with aurora kinase inhibition and targeted therapy offers a promising strategy to overcome lung cancer drug resistance.
Keywords:
CancerCell biologyDrug therapyLung cancerMetabolism

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