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CRISPR activation screens identify oncogenic lncRNAs that are susceptible to CDK4/6 inhibitor treatment

Yifei Wang1, Yueshan Zhao1, Jiaxin Hu1

  • 1Center for Pharmacogenetics, Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA.

Nature Communications
|April 9, 2026
PubMed

Insights

Long non-coding RNAs (lncRNAs) influence breast cancer growth and drug response. Specific lncRNAs enhance sensitivity to CDK4/6 inhibitors, offering potential therapeutic biomarkers.

Area of Science:

  • Genomics
  • Cancer Biology
  • Molecular Oncology

Background:

  • The function of long non-coding RNAs (lncRNAs) in cancer development and treatment outcomes is not well understood.
  • Identifying regulatory elements influencing targeted therapies is crucial for improving cancer treatment.

Purpose of the Study:

  • To identify lncRNAs that modulate breast cancer cell response to palbociclib, a CDK4/6 inhibitor.
  • To explore the correlation between lncRNA-driven tumor proliferation and sensitivity to CDK4/6 inhibitors.

Main Methods:

  • Genome-wide and focused CRISPR activation screens were employed to identify regulatory lncRNAs.
  • A two-stage proliferation screen was utilized to assess tumor growth and drug sensitivity.
  • CRISPRa screen data was integrated with drug response profiles from 815 cancer cell lines.

Main Results:

  • A negative correlation was observed between lncRNA-mediated tumor proliferation and CDK4/6 inhibitor sensitivity.
  • TENM3-AS1, LINC01117, and ENSG00000226706 were identified as lncRNAs that increase breast cancer sensitivity to CDK4/6 inhibitors while promoting proliferation.
  • These lncRNA signatures correlated with CDK4/6 inhibitor response in breast cancer patients.
  • TENM3-AS1 was identified as an ERα-interacting lncRNA, with its effect on drug sensitivity dependent on ERα expression.

Conclusions:

  • Specific lncRNAs can enhance sensitivity to CDK4/6 inhibitors in breast cancer.
  • TENM3-AS1's mechanism involves interaction with ERα, influencing drug response.
  • These oncogenic lncRNAs represent potential predictive biomarkers for CDK4/6 inhibitor therapy in cancer.

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