Zhou Danyang, Liu Wei, Zhang Yanyan, Li Chong
Department of Oncology, The Affiliated Dazu's Hospital of Chongqing Medical University, Chongqing 402360, China.
Department of Respiratory, Nanjing First Hospital, China Pharmaceutical University, Nanjing 210012, China.
Biomedicines. 2025 Apr 14;13(4):958. doi: 10.3390/biomedicines13040958.
: PARP inhibitors (PARPi) are pivotal to treating homologous recombination repair-deficient (HRD) cancers, particularly -mutated ovarian and breast cancers. However, most ovarian and breast cancers harbor wild-type (WT) , limiting PARPi eligibility. This study aims to identify an approved drug that could induce a BRCAness phenotype, thereby sensitizing WT BRCA cancers to PARPi. : Ovarian and breast cancer cell lines with WT were treated with ivosidenib. HR repair efficiency was assessed via RAD51 foci formation and reporter assays. Synthetic lethality with PARPi was evaluated using viability and colony formation assays. Mechanistic studies included RNA-binding protein pulldown, co-immunoprecipitation, and functional analyses of DNA repair pathways. YTHDC2's role in HR was investigated through siRNA knockdown and rescue experiments. : Ivosidenib significantly reduced HR repair efficiency and sensitized cells to PARPi, inducing synthetic lethality. Mechanistically, ivosidenib directly bound YTHDC2, an m6A reader critical for HR. This interaction disrupted YTHDC2's ability to promote DNA double-strand break repair via HR, evidenced by impaired recruitment of repair proteins (e.g., BRCA1, RAD51) and accumulation of DNA damage (γH2AX foci). YTHDC2 knockdown phenocopied ivosidenib effects, while overexpression rescued HR defects. : Ivosidenib induces BRCAness in WT BRCA ovarian and breast cancers by targeting YTHDC2, thereby suppressing HR repair and enhancing PARPi sensitivity. This uncovers a novel, metabolism-independent mechanism of ivosidenib, repositioning it as a therapeutic agent for HRD tumors. These findings propose a strategy to expand PARPi eligibility to WT BRCA cancers, addressing a critical unmet need in oncology.
聚（ADP-核糖）聚合酶抑制剂（PARPi）对于治疗同源重组修复缺陷（HRD）癌症至关重要，尤其是BRCA突变的卵巢癌和乳腺癌。然而，大多数卵巢癌和乳腺癌携带野生型（WT）BRCA，限制了PARPi的适用范围。本研究旨在确定一种已获批的药物，该药物可诱导BRCAness表型，从而使WT BRCA癌症对PARPi敏感。
将携带WT BRCA的卵巢癌和乳腺癌细胞系用艾伏尼布处理。通过RAD51灶形成和报告基因检测评估HR修复效率。使用活力和集落形成检测评估与PARPi的合成致死性。机制研究包括RNA结合蛋白下拉、免疫共沉淀以及DNA修复途径的功能分析。通过siRNA敲低和拯救实验研究YTHDC2在HR中的作用。
艾伏尼布显著降低HR修复效率并使细胞对PARPi敏感，诱导合成致死性。机制上，艾伏尼布直接结合YTHDC2，YTHDC2是一种对HR至关重要的m6A阅读器。这种相互作用破坏了YTHDC2通过HR促进DNA双链断裂修复的能力，表现为修复蛋白（如BRCA1、RAD51）募集受损和DNA损伤（γH2AX灶）积累。YTHDC2敲低模拟了艾伏尼布的作用，而过表达则挽救了HR缺陷。
艾伏尼布通过靶向YTHDC2在WT BRCA卵巢癌和乳腺癌中诱导BRCAness，从而抑制HR修复并增强PARPi敏感性。这揭示了艾伏尼布一种新的、不依赖代谢的机制，将其重新定位为HRD肿瘤的治疗药物。这些发现提出了一种将PARPi适用范围扩大到WT BRCA癌症的策略，满足了肿瘤学中一个关键的未满足需求。
