Taletrectinib promotes pyroptosis in colorectal carcinoma via SRC/AKT/mTOR axis inhibition
Abstract 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 ai...
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Nature Portfolio
2025-05-01
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| Online Access: | https://doi.org/10.1038/s41598-025-02901-3 |
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| author | Ting Zhang Ye Zou Sun-Han Zhang Yuan-Yi Wang Shuang He Wei Yuan Min Yang Teng Liu Shi-Hua Deng Dong-Ming Wu Ying Xu |
| author_facet | Ting Zhang Ye Zou Sun-Han Zhang Yuan-Yi Wang Shuang He Wei Yuan Min Yang Teng Liu Shi-Hua Deng Dong-Ming Wu Ying Xu |
| author_sort | Ting Zhang |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-bae680a6d2c44db3b05f67d463867717 |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-bae680a6d2c44db3b05f67d4638677172025-08-20T02:29:50ZengNature PortfolioScientific Reports2045-23222025-05-0115111410.1038/s41598-025-02901-3Taletrectinib promotes pyroptosis in colorectal carcinoma via SRC/AKT/mTOR axis inhibitionTing Zhang0Ye Zou1Sun-Han Zhang2Yuan-Yi Wang3Shuang He4Wei Yuan5Min Yang6Teng Liu7Shi-Hua Deng8Dong-Ming Wu9Ying Xu10School of Clinical Medicine, The First Affiliated Hospital of Chengdu Medical CollegeSchool of Clinical Medicine, Chengdu Medical CollegeSchool of Clinical Medicine, Chengdu Medical CollegeSchool of Clinical Medicine, Chengdu Medical CollegeSchool of Clinical Medicine, Chengdu Medical CollegeSchool of Clinical Medicine, Chengdu Medical CollegeSchool of Clinical Medicine, The First Affiliated Hospital of Chengdu Medical CollegeSchool of Clinical Medicine, The First Affiliated Hospital of Chengdu Medical CollegeSchool of Clinical Medicine, The First Affiliated Hospital of Chengdu Medical CollegeSchool of Clinical Medicine, The First Affiliated Hospital of Chengdu Medical CollegeSchool of Clinical Medicine, The First Affiliated Hospital of Chengdu Medical CollegeAbstract 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.https://doi.org/10.1038/s41598-025-02901-3Colorectal carcinomaTaletrectinibPyroptosisGSDMESRC |
| spellingShingle | Ting Zhang Ye Zou Sun-Han Zhang Yuan-Yi Wang Shuang He Wei Yuan Min Yang Teng Liu Shi-Hua Deng Dong-Ming Wu Ying Xu Taletrectinib promotes pyroptosis in colorectal carcinoma via SRC/AKT/mTOR axis inhibition Scientific Reports Colorectal carcinoma Taletrectinib Pyroptosis GSDME SRC |
| title | Taletrectinib promotes pyroptosis in colorectal carcinoma via SRC/AKT/mTOR axis inhibition |
| title_full | Taletrectinib promotes pyroptosis in colorectal carcinoma via SRC/AKT/mTOR axis inhibition |
| title_fullStr | Taletrectinib promotes pyroptosis in colorectal carcinoma via SRC/AKT/mTOR axis inhibition |
| title_full_unstemmed | Taletrectinib promotes pyroptosis in colorectal carcinoma via SRC/AKT/mTOR axis inhibition |
| title_short | Taletrectinib promotes pyroptosis in colorectal carcinoma via SRC/AKT/mTOR axis inhibition |
| title_sort | taletrectinib promotes pyroptosis in colorectal carcinoma via src akt mtor axis inhibition |
| topic | Colorectal carcinoma Taletrectinib Pyroptosis GSDME SRC |
| url | https://doi.org/10.1038/s41598-025-02901-3 |
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