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Long non-coding RNA LRTOR drives osimertinib resistance in non-small cell lung cancer by boosting YAP positive

Zhimin Miao1, Zhou Sha2, Jianzhong He3

  • 1State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao SAR 999078, China; Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Taipa, Macao SAR 999078, China.

Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy
|May 2, 2025
PubMed

Insights

A novel long non-coding RNA, LRTOR, drives osimertinib resistance in EGFR-mutant lung cancer by stabilizing YAP. Targeting LRTOR may restore sensitivity to osimertinib in non-small cell lung cancer patients.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Acquired resistance limits osimertinib (OSI) efficacy in EGFR-mutant lung cancer.
  • Mechanisms underlying OSI resistance in non-small cell lung cancer (NSCLC) are not fully understood.

Purpose of the Study:

  • Identify novel mechanisms driving OSI resistance in NSCLC.
  • Investigate the role of long non-coding RNAs (lncRNAs) in OSI resistance.
  • Explore LRTOR as a potential therapeutic target for overcoming OSI resistance.

Main Methods:

  • Analysis of clinical data to correlate LRTOR expression with patient prognosis.
  • In vitro and in vivo functional studies to assess LRTOR's impact on tumor growth and OSI resistance.
  • Mechanistic studies involving YAP, LATS, KCMF1, and YAP/TEAD1 complex formation.
  • siRNA-mediated depletion of LRTOR in patient-derived organoid xenograft models.

Main Results:

  • Elevated LRTOR expression is associated with poor prognosis in OSI-resistant NSCLC patients.
  • LRTOR promotes tumor growth and confers OSI resistance.
  • LRTOR stabilizes YAP by preventing LATS-mediated phosphorylation and degradation.
  • LRTOR enhances YAP nuclear translocation and YAP/TEAD1 complex formation, creating a positive feedback loop.
  • LRTOR depletion restores OSI sensitivity in resistant NSCLC models.

Conclusions:

  • LRTOR is a key driver of acquired osimertinib resistance in EGFR-mutant NSCLC.
  • The LRTOR/YAP signaling axis represents a novel mechanism of OSI resistance.
  • LRTOR is a promising therapeutic and prognostic target for overcoming acquired OSI resistance in lung cancer.
Keywords:
Long non-coding RNANon-small cell lung cancerOsimertinib resistanceYes-associated protein

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