Tinengotinib (TT-00420) inhibits tumor growth and overcomes multidrug resistance in gastrointestinal cancers.

Gastrointestinal malignancies have a high incidence and mortality rates worldwide; however, treatment challenges persist, including the lack of effective targets, limited therapeutic options, and primary and acquired resistance. Tinengotinib (TT-00420), an innovative multi-target kinase inhibitor developed by TransThera Sciences (Nanjing), Inc., has demonstrated strong antitumor activity in breast cancer, cholangiocarcinoma, and small cell lung cancer, but its therapeutic potential in gastrointestinal cancers has not been fully explored. In this study, human gastric cancer and colorectal cancer cell lines, together with patient-derived xenograft, cell line-derived xenograft, and patient-derived organoid models, were used to comprehensively evaluate the antitumor efficacy of TT-00420 in regulating tumor growth. In addition, trastuzumab-resistant and immunotherapy-resistant models were established to assess the antitumor activity of TT-00420 in treatment-refractory settings. TT-00420 effectively suppressed tumor growth in both gastric and colorectal cancer PDX models while maintaining a favorable safety profile and demonstrated robust efficacy in trastuzumab-resistant and immunotherapy-resistant models. Mechanistically, Western blot analysis revealed that Aurora A expression was downregulated following TT-00420 treatment, and the IC50 of TT-00420 increased in AURKA-knockdown cell lines, suggesting that Aurora A contributes to the antitumor activity of TT-00420. Collectively, these findings indicate that TT-00420 is a highly promising antitumor agent with potent efficacy against gastric and colorectal cancers, providing a potential therapeutic strategy for gastrointestinal malignancies and offering valuable insights for future clinical research.