Anti-EGFR therapy in metastatic colorectal cancer: mechanisms and potential regimens of drug resistance.
Qing-Hai LiYing-Zhao WangJian TuChu-Wei LiuYu-Jie YuanRun LinWei-Ling HeShi-Rong CaiYu-Long HeJin-Ning YePublished in: Gastroenterology report (2020)
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.
Keyphrases
- metastatic colorectal cancer
- epidermal growth factor receptor
- tyrosine kinase
- growth factor
- wild type
- signaling pathway
- advanced non small cell lung cancer
- protein kinase
- cell death
- cell proliferation
- small cell lung cancer
- pi k akt
- dna methylation
- clinical practice
- gene expression
- type diabetes
- poor prognosis
- transcription factor
- stem cells
- metabolic syndrome
- squamous cell carcinoma
- epithelial mesenchymal transition
- induced apoptosis
- genome wide
- single molecule
- long non coding rna
- cancer therapy
- weight loss
- bone marrow
- replacement therapy
- radiation therapy
- locally advanced