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<p>Resistance to poly-(ADP)-ribose polymerase inhibitors (PARPi) remains a significant challenge in clinical practice, leading to treatment failure in many patients. It is crucial to better understand the molecular mechanisms that underlie PARPi resistance. In this study, utilizing a genome-wide CRISPR activation screen with olaparib, we identified ARL11 as a potential modulator of PARPi treatment response in BRCA-wild-type MDA-MB-231 cells. Mechanistically, ARL11 interacts with STING to enhance innate immunity and forms positive feedback with type I interferon (IFN) induction, which induces ARL11 up-regulation and contributes to resistance to PARPi therapy. Additionally, we observed that ARL11 interacts with the RUVBL1 and RUVBL2 (RUVBL1/2) complex, the key DNA double-strand repair proteins, facilitating DNA homologous recombination (HR) repair and significantly reducing PARPi-induced DNA double-strand damages. Clinical sample analysis reveals that the expression levels of ARL11 and RUVBL1/2 are significantly elevated in breast cancer patients compared to healthy controls. Collectively, our findings suggested that ARL11 and RUVBL1/2 may be promising therapeutic targets to sensitize breast cancer cells to PARPi therapy.</p>

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Genome-wide CRISPR activation screen identifies ARL11 as a sensitivity determinant of PARP inhibitor therapy

  • 期刊论文

  • 发表日期：

    2025年3月23日

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  • Tengjiang Zhang,
  • Yuan Zhang,
  • Xuxiang Wang,
  • Haitian Hu,
  • Christopher G. Lin,
  • Yaru Xu,
  • Hanqiu Zheng

摘要

Resistance to poly-(ADP)-ribose polymerase inhibitors (PARPi) remains a significant challenge in clinical practice, leading to treatment failure in many patients. It is crucial to better understand the molecular mechanisms that underlie PARPi resistance. In this study, utilizing a genome-wide CRISPR activation screen with olaparib, we identified ARL11 as a potential modulator of PARPi treatment response in BRCA-wild-type MDA-MB-231 cells. Mechanistically, ARL11 interacts with STING to enhance innate immunity and forms positive feedback with type I interferon (IFN) induction, which induces ARL11 up-regulation and contributes to resistance to PARPi therapy. Additionally, we observed that ARL11 interacts with the RUVBL1 and RUVBL2 (RUVBL1/2) complex, the key DNA double-strand repair proteins, facilitating DNA homologous recombination (HR) repair and significantly reducing PARPi-induced DNA double-strand damages. Clinical sample analysis reveals that the expression levels of ARL11 and RUVBL1/2 are significantly elevated in breast cancer patients compared to healthy controls. Collectively, our findings suggested that ARL11 and RUVBL1/2 may be promising therapeutic targets to sensitize breast cancer cells to PARPi therapy.