E7820 和 Indisulam (E7070) 是磺酰胺分子胶，通过与 E3 连接酶接头 DCAF15 形成三元复合物来降解剪接因子 RBM39，从而调节 RNA 剪接。为了确定 E7820 抗肿瘤功效的生物标志物，我们对 42 名实体瘤患者建立的患者来源的异种移植 (PDX) 小鼠模型进行了治疗。总体缓解率为 38.1%（16 个 PDX），并且在各种肿瘤类型中观察到肿瘤消退。 PDX基因组的外显子组测序显示，同源重组修复（HRR）系统（例如ATM）基因的功能丧失突变在对E7820有反应的肿瘤中显着富集（p = 4.5 × 103）。有趣的是，在 BRCA2 功能障碍的肿瘤中，E7820 介导的 DNA 双链断裂增加，敲低 BRCA1/2 转录本或敲除 ATM、ATR 或 BAP1 会使癌细胞对 E7820 敏感。转录组学分析表明，E7820 处理导致 mRNA 内含子保留并减少转录，尤其是 HRR 基因。这种诱导的 HRR 功能障碍可能导致具有同源重组缺陷 (HRD) 的肿瘤细胞的综合致死性。此外，E7820与奥拉帕尼联合发挥协同作用，E7820甚至对奥拉帕尼耐药细胞系也有效。总之，HRD 是 E7820 疗效的一种有前途的预测生物标志物，并且具有改善 HRD 阳性癌症患者预后的巨大潜力。© 2024。作者。

E7820 and Indisulam (E7070) are sulfonamide molecular glues that modulate RNA splicing by degrading the splicing factor RBM39 via ternary complex formation with the E3 ligase adaptor DCAF15. To identify biomarkers of the antitumor efficacy of E7820, we treated patient-derived xenograft (PDX) mouse models established from 42 patients with solid tumors. The overall response rate was 38.1% (16 PDXs), and tumor regression was observed across various tumor types. Exome sequencing of the PDX genome revealed that loss-of-function mutations in genes of the homologous recombination repair (HRR) system, such as ATM, were significantly enriched in tumors that responded to E7820 (p = 4.5 × 103). Interestingly, E7820-mediated double-strand breaks in DNA were increased in tumors with BRCA2 dysfunction, and knockdown of BRCA1/2 transcripts or knockout of ATM, ATR, or BAP1 sensitized cancer cells to E7820. Transcriptomic analyses revealed that E7820 treatment resulted in the intron retention of mRNAs and decreased transcription, especially for HRR genes. This induced HRR malfunction probably leads to the synthetic lethality of tumor cells with homologous recombination deficiency (HRD). Furthermore, E7820, in combination with olaparib, exerted a synergistic effect, and E7820 was even effective in an olaparib-resistant cell line. In conclusion, HRD is a promising predictive biomarker of E7820 efficacy and has a high potential to improve the prognosis of patients with HRD-positive cancers.© 2024. The Author(s).