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<p>Mutational inactivation of the tumor suppressor gene <i>ARID1A</i> is a key driver of tumorigenesis in various types of cancer, making it a promising therapeutic target for anticancer drug development. Here, we performed a synthetic lethal drug screening in an approved drug library with ARID1A isogenic CRC cell lines and identified estramustine phosphate sodium (EMP), an FDA approved antimicrotubule chemotherapy drug, as a synthetic lethal partner of ARID1A. ARID1A loss increases the vulnerability to EMP. Mechanistically, ARID1A loss increases the phosphorylation level of MAP4 (microtubule-associated protein 4), which is a key microtubule dynamics regulator in cancer cells. Therefore, ARID1A loss attenuates microtubule stabilizing activity of MAP4 and creates a dependence on its residual activity. By targeting MAP4, EMP severely disrupts microtubule dynamics, affecting bipolar spindle formation and positioning, and inducing mitotic cell death in ARID1A-deficient cells. Furthermore, we identified that MAP4 is phosphorylated by PI3K, which is activated by ARID1A loss. These findings highlight MAP4 as a key regulator of microtubule dynamics in ARID1A-deficient cells and unveil a novel synthetic lethality relationship between ARID1A and EMP.</p>

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MAP4 phosphorylation induced by ARID1A loss sensitizes colorectal cancer cells to EMP

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月8日

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  • Lei Pan,
  • Danzhu Wu,
  • Yilin He,
  • Kejin Wang,
  • Yingyi Zeng,
  • Cheng Xiang,
  • Lifang Huang,
  • Wenjie Qin,
  • Xu Zhang,
  • Zihuan Wang,
  • Yingnan Yu,
  • Zhen Wang,
  • Li Xiang,
  • Changjie Wu,
  • Aimin Li

摘要

Mutational inactivation of the tumor suppressor gene ARID1A is a key driver of tumorigenesis in various types of cancer, making it a promising therapeutic target for anticancer drug development. Here, we performed a synthetic lethal drug screening in an approved drug library with ARID1A isogenic CRC cell lines and identified estramustine phosphate sodium (EMP), an FDA approved antimicrotubule chemotherapy drug, as a synthetic lethal partner of ARID1A. ARID1A loss increases the vulnerability to EMP. Mechanistically, ARID1A loss increases the phosphorylation level of MAP4 (microtubule-associated protein 4), which is a key microtubule dynamics regulator in cancer cells. Therefore, ARID1A loss attenuates microtubule stabilizing activity of MAP4 and creates a dependence on its residual activity. By targeting MAP4, EMP severely disrupts microtubule dynamics, affecting bipolar spindle formation and positioning, and inducing mitotic cell death in ARID1A-deficient cells. Furthermore, we identified that MAP4 is phosphorylated by PI3K, which is activated by ARID1A loss. These findings highlight MAP4 as a key regulator of microtubule dynamics in ARID1A-deficient cells and unveil a novel synthetic lethality relationship between ARID1A and EMP.