背景:酪氨酸激酶抑制剂(TKIs)在晚期结直肠癌(CRC)的靶向治疗中至关重要。安洛替尼,多目标TKI,先前已在先前的研究中被证明具有治疗益处。环状RNA(circularRNAs,circRNAs)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。靶向治疗时代与circRNAs相关的详细分子机制和特异性生物标志物,然而,保持模糊。
方法:进行全转录组RNA测序和功能实验以鉴定候选的安洛替尼调节的circRNAs,其机制已被分子生物学实验证实。CircHAS2在小鼠中的患者来源的CRC类器官(n=22)和患者来源的CRC肿瘤的文库中进行剖析。此外,我们开始了一项针对14例接受安洛替尼治疗的晚期CRC患者的前瞻性II期临床研究,以验证药物敏感性(ClinicalTrials.gov标识符:NCT05262335).
结果:安洛替尼通过下调circHAS2在体外和体内抑制肿瘤生长。CircHAS2通过充当miR-1244的海绵并与USP10结合以促进p53核输出以及降解来调节CCNE2激活。并行,cirhas2作为预测安洛替尼敏感性的有效生物标志物,在患者来源的类器官和异种移植模型中。此外,在circHAS2水平较高的患者中,将安洛替尼纳入治疗方案的疗效可产生有意义的临床缓解.我们的发现为大约52.9%的circHAS2水平高的晚期CRC患者提供了一个有希望的靶向策略。
结论: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洛替尼的敏感性。此外,我们的初步II期临床研究,涉及接受安洛替尼治疗的晚期CRC患者,证实circHAS2为潜在的敏感性标记。
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.