摘要
作为表皮生长因子受体(EGFR)的高效靶向药物,西妥昔单抗和帕尼单抗常用于转移性结直肠癌(mCRC)患者的临床治疗。尽管这些药物取得良好的疗效,但耐药现象也常伴相随。目前,研究人员已经明确了KRAS、NRAS、BRAF突变以及HER2扩增对上述药物疗效的影响,并提出了相应的对策。但EGFR及其配体的异常,PIK3CA、PTEN、TP53、MET、HER3、IRS2、FGFR1和MAP2K1等基因的突变或扩增,胰岛素生长因子-1(IGF-1)的过表达,Bcl-2介导的细胞凋亡调节蛋白(Bim)的低表达,错配修复基因缺陷(dMMR),以及表观遗传不稳定等因素,也可导致mCRC的耐药。尽管耐药的出现具有遗传或表观遗传的异质性,但上述与此有关的分子改变大都集中在某些关键的信号通路上,如RAS/RAF/MAPK通路和PI3K/Akt/mTOR通路。因此,许多研究开始尝试靶向这些信号以期开发出新的治疗方案。本文中,我们对抗EGFR治疗耐药性的产生机制进行了综述,并提出了临床实践中的潜在对策。
Cetuximab and panitumumab,as the highly effective antibodies targeting epidermal growth factor receptor(EGFR),have clinical activity in the patients with metastatic colorectal cancer(mCRC).These agents have good curative efficacy,but drug resistance also exists at the same time.The effects of KRAS,NRAS,and BRAF mutations and HER2 amplification on the treatment of refractory mCRC have been elucidated and the corresponding countermeasures have been put forward.However,the changes in EGFR and its ligands,the mutations or amplifications of PIK3CA,PTEN,TP53,MET,HER3,IRS2,FGFR1,and MAP2K1,the overexpression of insulin growth factor-1,the low expression of Bcl-2-interacting mediator of cell death,mismatch repair-deficient,and epigenetic instability may also lead to drug resistance in mCRC.Although the emergence of drug resistance has genetic or epigenetic heterogeneity,most of these molecular changes relating to it are focused on the key signaling pathways,such as the RAS/RAF/mitogen-activated protein kinase or phosphatidylinositol 3-kinase/Akt/mammalian target of the rapamycin pathway.Accordingly,numerous efforts to target these signaling pathways and develop the novel therapeutic regimens have been carried out.Herein,we have reviewed the underlying mechanisms of the resistance to anti-EGFR therapy and the possible implications in clinical practice.
基金
supported by the National Natural Science Foundation of China[81871994 and 81701834]
the Guangdong Natural Science Foundation[2019B151502063]
the Guangdong Science and Technology Planning Program[20190202018].