Yamamoto Kazumasa, Nakayama Izuma, Shitara Kohei
Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba 277-8577, Japan.
Ther Adv Med Oncol. 2025 Jun 16;17:17588359251344804. doi: 10.1177/17588359251344804. eCollection 2025.
Human epidermal growth factor receptor 2 was the first successful molecular target in treating gastric cancer, marking a significant milestone for targeted therapies. Emerging evidence on Claudin18.2 (CLDN18.2) has recently reshaped the paradigm of therapeutic targets, expanding the focus beyond conventional oncogenic drivers. Therapeutic strategies now target tumor-associated molecules which highly expressed in tumors but are not necessarily critical for tumor growth or survival. Molecules such as trophoblast cell surface antigen 2, Caprin-1, and Nectin-4 are promising non-oncogenic targets for advanced gastric cancer treatment. Innovative therapeutic approaches, such as antibody-drug conjugates, bispecific antibodies, and chimeric antigen receptor T-cell therapy, have accelerated the potential of targeting tissue-associated antigens. This review provides an update on CLDN18.2-directed therapies and explores the development of novel therapeutic strategies targeting non-oncogenic drivers. In addition, we discuss ongoing challenges, including biomarker overlap, resistance mechanisms, and future directions for next-generation molecular targeted therapy in gastric cancer.
人表皮生长因子受体2是治疗胃癌的首个成功分子靶点，标志着靶向治疗的一个重要里程碑。最近，关于Claudin18.2（CLDN18.2）的新证据重塑了治疗靶点的模式，将关注点扩展到了传统致癌驱动因素之外。现在的治疗策略针对的是在肿瘤中高表达但不一定对肿瘤生长或存活至关重要的肿瘤相关分子。滋养层细胞表面抗原2、Caprin-1和Nectin-4等分子是晚期胃癌治疗中很有前景的非致癌靶点。抗体药物偶联物、双特异性抗体和嵌合抗原受体T细胞疗法等创新治疗方法加速了靶向组织相关抗原的潜力。本综述提供了关于CLDN18.2导向疗法的最新信息，并探讨了针对非致癌驱动因素的新型治疗策略的发展。此外，我们还讨论了当前面临的挑战，包括生物标志物重叠、耐药机制以及胃癌下一代分子靶向治疗的未来方向。
