Tyrosine kinase inhibitors (TKIs) are crucial in the targeted treatment of advanced colorectal cancer (CRC). Anlotinib, a multi-target TKI, has previously been demonstrated to offer therapeutic benefits in previous studies. Circular RNAs (circRNAs) have been implicated in CRC progression and their unique structural stability serves as promising biomarkers. The detailed molecular mechanisms and specific biomarkers related to circRNAs in the era of targeted therapies, however, remain obscure. The whole transcriptome RNA sequencing and function experiments were conducted to identify candidate anlotinib-regulated circRNAs, whose mechanism was confirmed by molecular biology experiments. CircHAS2 was profiled in a library of patient-derived CRC organoids (n = 22) and patient-derived CRC tumors in mice. Furthermore, a prospective phase II clinical study of 14 advanced CRC patients with anlotinib-based therapy was commenced to verify drug sensitivity (ClinicalTrials.gov identifier: NCT05262335). Anlotinib inhibits tumor growth in vitro and in vivo by downregulating circHAS2. CircHAS2 modulates CCNE2 activation by acting as a sponge for miR-1244, and binding to USP10 to facilitate p53 nuclear export as well as degradation. In parallel, circHAS2 serves as a potent biomarker predictive of anlotinib sensitivity, both in patient-derived organoids and xenograft models. Moreover, the efficacy of anlotinib inclusion into the treatment regimen yields meaningful clinical responses in patients with high levels of circHAS2. Our findings offer a promising targeted strategy for approximately 52.9% of advanced CRC patients who have high circHAS2 levels. CircHAS2 promotes cell proliferation via the miR-1244/CCNE2 and USP10/p53/CCNE2 bidirectional axes. Patient-derived organoids and xenograft models are employed to validate the sensitivity to anlotinib. Furthermore, our preliminary Phase II clinical study, involving advanced CRC patients treated with anlotinib, confirmed circHAS2 as a potential sensitivity marker.

中文翻译：

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CircHAS2激活CCNE2促进细胞增殖并使结直肠癌对安罗替尼的反应敏感

酪氨酸激酶抑制剂（TKI）对于晚期结直肠癌（CRC）的靶向治疗至关重要。安罗替尼是一种多靶点 TKI，之前的研究已被证明具有治疗益处。环状 RNA (circRNA) 与 CRC 进展有关，其独特的结构稳定性可作为有前途的生物标志物。然而，在靶向治疗时代，与 circRNA 相关的详细分子机制和特定生物标志物仍然不清楚。通过全转录组RNA测序和功能实验来鉴定候选安罗替尼调控的circRNA，其机制得到分子生物学实验的证实。在患者来源的 CRC 类器官 (n = 22) 和小鼠体内患者来源的 CRC 肿瘤文库中对 CircHAS2 进行了分析。此外，一项前瞻性 II 期临床研究已开始，对 14 名晚期 CRC 患者进行基于安罗替尼的治疗，以验证药物敏感性（ClinicalTrials.gov 标识符：NCT05262335）。安罗替尼通过下调 circHAS2 抑制体外和体内肿瘤生长。 CircHAS2 通过充当 miR-1244 的海绵并与 USP10 结合以促进 p53 核输出和降解来调节 CCNE2 激活。与此同时，在患者来源的类器官和异种移植模型中，circHAS2 可以作为预测安罗替尼敏感性的有效生物标志物。此外，将安罗替尼纳入治疗方案的疗效在 circHAS2 水平高的患者中产生了有意义的临床反应。我们的研究结果为大约 52.9% 具有高 circHAS2 水平的晚期 CRC 患者提供了一个有前景的靶向策略。 CircHAS2 通过 miR-1244/CCNE2 和 USP10/p53/CCNE2 双向轴促进细胞增殖。采用患者来源的类器官和异种移植模型来验证对安罗替尼的敏感性。此外，我们的初步 II 期临床研究涉及接受安罗替尼治疗的晚期 CRC 患者，证实 circHAS2 是一种潜在的敏感性标记物。