靶向SRC治疗胰腺癌的研究新进展

Recent progress in SRC targeted therapy for pancreatic cancer

胰腺癌(pancreatic cancer,PC)致死率极高,对化疗药物高度耐受,患者5年生存率仅为10%.因此,寻找有效的PC治疗药物是当今世界性难题.SRC是一种原癌基因酪氨酸蛋白激酶,在超过70%的PC中呈高表达或高活性状态,参与调控PC细胞增殖、浸润、转移及肿瘤血管生成,是研发PC治疗药物最有希望的分子靶点之一.大量临床前研究证实,小分子SRC抑制剂在体内和体外实验中表现出强大的抗PC活性,而且与常规化疗药物协同作用逆转PC耐药.一些SRC抑制剂已经进入PC治疗的临床试验.靶向SRC治疗PC具有广阔的应用前景.本文分析SRC对PC的调控机制以及靶向SRC治疗PC的新进展和存在问题.作者认为应用精准医学原则指导SRC抑制剂临床试验设计、联合应用免疫治疗、研发更高选择性和更高活性的SRC抑制剂以及对SRC调控网络进一步探讨,可为靶向SRC治疗PC带来突破.

Pancreatic cancer(PC)is a highly lethal malignancy with a 5-year survival rate of only 10%and is extremely resistant to chemotherapy.Therefore,developing effective therapeutic drugs is urgently needed.SRC is a proto-oncogenic tyrosine protein kinase and highly expressed in more than 70%of PCs.SRC is involved in regulating the proliferation,infiltration,and metastasis of PC cells as well as tumor angiogenesis,thus representing one of the most promising molecular targets for developing novel drugs.Preclinical studies demonstrate that small-molecule SRC inhibitors display significant anti-cancer activities in vitro and in vivo,and have a synergistic effect with conventional chemotherapy drugs against PC.Some SRC inhibitors have been evaluated in clinical trials.This article analyzes the regulatory mechanism of SRC and the recent progress and problems in developing drugs targeting SRC for the treatment of PC.Unfortunately,up to date no SRC inhibitor or regiment containing SRC inhibitors has been approved for the clinical treatment of PC.In the authors’opinion,the introduction of precision medicine principles to carry out SRC inhibitor clinical trials,combination of immunotherapy and SRC inhibitors,seeking more selective and effective SRC inhibitors,and further exploration of the SRC regulatory network may be the future directions for developing SRC-targeted therapies against PC.