Khelwatty Said A, Puvanenthiran Soozana, Seddon Alan M, Bagwan Izhar, Essapen Sharadah, Modjtahedi Helmout
School of Life Science, Pharmacy and Chemistry, Kingston University London, London KT1 2EE, UK.
Faculty of health and Life Sciences, Oxford Brookes University, Oxford OX3 0BP, UK.
Cancers (Basel). 2025 Aug 28;17(17):2810. doi: 10.3390/cancers17172810.
Colorectal cancer (CRC) remains a significant global health burden. While early-stage CRC has a high survival rate, most patients are diagnosed with advanced disease, necessitating more effective and less toxic therapeutic targets. This review examines recent advancements, challenges, and future directions in targeted therapies for CRC, focusing on HER inhibitors. We assess the efficacy of monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) and explore strategies to overcome resistance mechanisms. Targeted therapies like cetuximab and panitumumab have improved outcomes for CRC patients with wild-type KRAS. However, resistance mechanisms and intra- and inter-tumour heterogeneity limit their effectiveness. Recent advancements include the development of dual TKIs, antibody/drug conjugates (ADCs), bispecific antibodies, and CAR-T cells against HER family members and other targets that are showing promise in preclinical and clinical trials. Targeted therapies have transformed CRC treatment, but more research is needed to overcome some of the current challenges, such as late diagnosis and the heterogenous nature of CRC, as well as the discovery of more reliable biomarkers for response to the therapy and patient selection. Future research should focus on identifying novel biomarkers of diagnostic, prognostic, and predictive value, developing next-generation inhibitors, drug repurposing, and combining small-molecule targeted therapies with immunotherapy. Such advances could ultimately help increase both the treatment options and outcomes for patients with CRC.
结直肠癌（CRC）仍然是一项重大的全球健康负担。虽然早期结直肠癌的生存率很高，但大多数患者被诊断为晚期疾病，因此需要更有效且毒性更小的治疗靶点。本综述探讨了结直肠癌靶向治疗的最新进展、挑战和未来方向，重点关注HER抑制剂。我们评估了单克隆抗体（mAb）和酪氨酸激酶抑制剂（TKI）的疗效，并探索克服耐药机制的策略。西妥昔单抗和帕尼单抗等靶向治疗改善了野生型KRAS结直肠癌患者的预后。然而，耐药机制以及肿瘤内和肿瘤间的异质性限制了它们的有效性。最近的进展包括开发针对HER家族成员和其他靶点的双靶点TKI、抗体/药物偶联物（ADC）、双特异性抗体和嵌合抗原受体T细胞（CAR-T），这些在临床前和临床试验中显示出了前景。靶向治疗改变了结直肠癌的治疗方式，但仍需要更多研究来克服当前的一些挑战，如晚期诊断和结直肠癌的异质性，以及发现更可靠的治疗反应生物标志物和患者选择标准。未来的研究应侧重于识别具有诊断、预后和预测价值的新型生物标志物，开发下一代抑制剂，药物再利用，以及将小分子靶向治疗与免疫治疗相结合。这些进展最终可能有助于增加结直肠癌患者的治疗选择并改善治疗结果。
