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Updated: Jun 6, 2025

Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down
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Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down

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YY1 downregulation underlies therapeutic response to molecular targeted agents

Shichao Zhou1,2, Jingyu Zang3, Mei-Chun Cai1

  • 1State Key Laboratory of Systems Medicine for Cancer, Department of Thoracic Surgery, Shanghai Cancer Institute, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Cell Death & Disease
|November 28, 2024
PubMed

Insights

Transcription factor Yin Yang 1 (YY1) drives cancer drug resistance by regulating cell cycle and autophagy. Inhibiting YY1 enhances targeted therapy efficacy and prevents resistance in lung cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Targeted cancer therapies face challenges from drug resistance.
  • The evolutionary path of cancer cells from drug-sensitive to resistant states is not fully understood.
  • Understanding molecular mechanisms of resistance is crucial for improving treatment outcomes.

Purpose of the Study:

  • To elucidate the molecular basis of therapy-induced cancer evolution and drug resistance.
  • To investigate the role of transcription factor Yin Yang 1 (YY1) in response to targeted kinase inhibitors.
  • To identify YY1 as a potential therapeutic target for overcoming drug resistance.

Main Methods:

  • Utilized a multifaceted approach including pharmacological inhibition of receptor tyrosine kinase (RTK)/mitogen-activated protein kinase (MAPK) pathways.
  • Assessed the transcriptional regulation and functional role of YY1.
  • Performed immunohistochemical analysis on clinical specimens of lung adenocarcinomas.

Main Results:

  • Pharmacological inhibition of RTK/MAPK pathways downregulated YY1 transcription, which resumed upon therapeutic escape.
  • Failure to decrease YY1 levels impaired cytotoxic effects and promoted resistance.
  • Eliminating residual YY1 maximized anticancer efficacy and prevented drug resistance.
  • YY1 was found to regulate cell cycle and autophagic programs.
  • YY1 was ubiquitously expressed in lung adenocarcinomas and showed dynamic changes with RTK/MAPK inhibition.

Conclusions:

  • Transcription factor YY1 plays a convergent role in the emergence of drug resistance across various targeted kinase inhibitors.
  • YY1 acts as a critical determinant node in the context of genotype-directed cancer therapies.
  • Targeting YY1 may represent a viable strategy to enhance the efficacy of targeted cancer treatments and overcome resistance.

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