Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Department of Medicine, University of Toronto, Toronto, ON, Canada.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
Lancet. 2020 Mar 28;395(10229):1078-1088. doi: 10.1016/S0140-6736(20)30164-1.
The identification of molecular targets and the growing knowledge of their cellular functions have led to the development of small molecule inhibitors as a major therapeutic class for cancer treatment. Both multitargeted and highly selective kinase inhibitors are used for the treatment of advanced treatment-resistant cancers, and many have also achieved regulatory approval for early clinical settings as adjuvant therapies or as first-line options for recurrent or metastatic disease. Lessons learned from the development of these agents can accelerate the development of next-generation inhibitors to optimise the therapeutic index, overcome drug resistance, and establish combination therapies. The future of small molecule inhibitors is promising as there is the potential to investigate novel difficult-to-drug targets, to apply predictive non-clinical models to select promising drug candidates for human evaluation, and to use dynamic clinical trial interventions with liquid biopsies to deliver precision medicine.
分子靶点的鉴定和对其细胞功能的不断深入了解，促使小分子抑制剂的发展成为癌症治疗的主要治疗类别。多靶点和高选择性激酶抑制剂都被用于治疗晚期治疗耐药的癌症，许多药物也已获得监管部门批准，可用于早期临床辅助治疗或作为复发性或转移性疾病的一线治疗选择。从这些药物的开发中吸取的经验教训可以加速下一代抑制剂的开发，以优化治疗指数、克服耐药性，并建立联合治疗。小分子抑制剂的前景是有希望的，因为有可能研究新的难以治疗的靶点，应用预测性非临床模型来选择有前途的候选药物进行人体评估，并使用液体活检进行动态临床试验干预来提供精准医学。
