Zhang Ting, Zou Ye, Zhang Sun-Han, Wang Yuan-Yi, He Shuang, Yuan Wei, Yang Min, Liu Teng, Deng Shi-Hua, Wu Dong-Ming, Xu Ying
School of Clinical Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, 610500, China.
School of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan, China.
Sci Rep. 2025 May 24;15(1):18049. doi: 10.1038/s41598-025-02901-3.
Drug resistance develops frequently after colorectal carcinoma (CRC) surgery, indicating the urgent need for new therapeutic strategies. Taletrectinib (DS-6051b/AB-106), a synthetic ROS1/NTRK inhibitor which has shown meaningful antitumor activity, is currently undergoing clinical trials aimed at addressing targeted resistance. However, the anti-cancer effect of taletrectinib on CRC remains unclear. In this study, our purpose was to evaluate taletrectinib-related cytotoxicity in vitro using two CRC cell lines, as well as in vivo in a mouse tumor model. The mechanism underlying the cytotoxicity of taletrectinib was evaluated using light microscopy, scanning electron microscopy, immunofluorescence assays, an annexin V-FITC/propidium iodide detection, lactate dehydrogenase (LDH) release assays, and western blotting. We found that the viability of CRC cells decreased with increasing concentrations of taletrectinib. In addition, transcriptome sequencing indicated that HCT116 and LOVO cell lines did not carry ROS1- or NTRK-related gene fusions and that the cytotoxic effect of taletrectinib was exerted via caspase-3/gasdermin E (GSDME)-dependent pyroptosis. Moreover, the effect of taletrectinib in promoting pyroptosis was reversed by treatment with the SRC agonist, tolimidone, both in vitro and in vivo. Overall, our findings suggest that taletrectinib suppresses tumor growth by inducing GSDME-mediated pyroptosis via the SRC/AKT/mTOR signaling pathway, indicating that taletrectinib shows potential as a promising therapeutic agent against CRC.
结直肠癌（CRC）手术后经常会出现耐药性，这表明迫切需要新的治疗策略。他雷替尼（DS-6051b/AB-106）是一种合成的ROS1/NTRK抑制剂，已显示出有意义的抗肿瘤活性，目前正在进行旨在解决靶向耐药性的临床试验。然而，他雷替尼对CRC的抗癌作用仍不清楚。在本研究中，我们的目的是使用两种CRC细胞系在体外以及在小鼠肿瘤模型中体内评估他雷替尼相关的细胞毒性。使用光学显微镜、扫描电子显微镜、免疫荧光测定、膜联蛋白V-FITC/碘化丙啶检测、乳酸脱氢酶（LDH）释放测定和蛋白质印迹法评估他雷替尼细胞毒性的潜在机制。我们发现，CRC细胞的活力随着他雷替尼浓度的增加而降低。此外，转录组测序表明，HCT116和LOVO细胞系不携带ROS1或NTRK相关基因融合，并且他雷替尼的细胞毒性作用是通过半胱天冬酶-3/gasdermin E（GSDME）依赖性细胞焦亡发挥的。此外，在体外和体内，用SRC激动剂托利米酮处理均可逆转他雷替尼促进细胞焦亡的作用。总体而言，我们的研究结果表明，他雷替尼通过SRC/AKT/mTOR信号通路诱导GSDME介导的细胞焦亡来抑制肿瘤生长，这表明他雷替尼作为一种有前景的抗CRC治疗药物具有潜力。
