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<p>The roles of long non-coding RNAs (lncRNAs) in tumorigenesis and therapeutic response remain largely unknown. Here we perform genome-wide and focused CRISPR activation screens to identify lncRNAs regulating palbociclib response in breast cancer cells. A synchronized two-stage proliferation screen not only characterizes tumor growth-regulating lncRNAs, but also reveals a strong negative correlation between lncRNA-mediated regulation of tumor proliferation and CDK4/6 inhibitor sensitivity. By integrating CRISPRa screen results with drug response data from 815 cancer cell lines, we identify and functionally validate that <i>TENM3-AS1</i>, <i>LINC01117</i>, and <i>ENSG00000226706</i> can increase breast cancer sensitivity to CDK4/6i while promoting tumor proliferation. In breast cancer patients, all three lncRNA signatures are associated with CDK4/6 inhibitor response. Mechanistically, we have shown that lncRNA <i>TENM3-AS1</i> is a potential ERα-interacting lncRNA, and its regulation of CDK4/6 inhibitor sensitivity is dependent on ERα expression. Our integrated strategy characterizes oncogenic lncRNAs as potential therapeutic biomarkers for CDK4/6 inhibitor treatment in cancer.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月9日

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  • Yifei Wang,
  • Yueshan Zhao,
  • Jiaxin Hu,
  • Zehua Wang,
  • Dhamotharan Pattarayan,
  • Sihan Li,
  • Yu Zhang,
  • Xiaofei Wang,
  • Yue Wang,
  • Wen Xie,
  • Min Zhang,
  • Da Yang

摘要

The roles of long non-coding RNAs (lncRNAs) in tumorigenesis and therapeutic response remain largely unknown. Here we perform genome-wide and focused CRISPR activation screens to identify lncRNAs regulating palbociclib response in breast cancer cells. A synchronized two-stage proliferation screen not only characterizes tumor growth-regulating lncRNAs, but also reveals a strong negative correlation between lncRNA-mediated regulation of tumor proliferation and CDK4/6 inhibitor sensitivity. By integrating CRISPRa screen results with drug response data from 815 cancer cell lines, we identify and functionally validate that TENM3-AS1, LINC01117, and ENSG00000226706 can increase breast cancer sensitivity to CDK4/6i while promoting tumor proliferation. In breast cancer patients, all three lncRNA signatures are associated with CDK4/6 inhibitor response. Mechanistically, we have shown that lncRNA TENM3-AS1 is a potential ERα-interacting lncRNA, and its regulation of CDK4/6 inhibitor sensitivity is dependent on ERα expression. Our integrated strategy characterizes oncogenic lncRNAs as potential therapeutic biomarkers for CDK4/6 inhibitor treatment in cancer.