Anti-EGFR therapy in metastatic colorectal cancer: mechanisms and potential regimens of drug resistance

Abstract

<jats:title>Abstract</jats:title> <jats:p>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.</jats:p>

<p>Up-and-Coming Experimental Drug Options for Metastatic Colorectal Cancer</p>

“…24 , 25 Other potential mechanisms for primary resistance to anti-EGFR antibodies include alterations in EGFR and EGFR ligands, NRAS mutations, BRAF mutations, and PIK3CA mutations, all of which propagate signaling despite EGFR blockade. 26 , 27 In addition to primary resistance, many patients will ultimately develop acquired resistance to anti-EGFR antibodies. Acquired resistance may occur due to secondary mutations in the signaling pathway or activation of parallel signaling pathways.…”

“…Up to 50% of patients treated with anti-EGFR antibodies will develop acquired resistance due to secondary KRAS mutations. 26 , 27 Secondary NRAS and BRAF mutations have also been implicated in acquired resistance. 26 , 27 Tumors may also take advantage of parallel signaling pathways to survive.…”

“… 26 , 27 Secondary NRAS and BRAF mutations have also been implicated in acquired resistance. 26 , 27 Tumors may also take advantage of parallel signaling pathways to survive. These pathways include the type 1 insulin-like growth factor receptor (IGF-1R), mesenchymal-epithelial transition factor receptor (MET receptor), and the human epidermal growth factor receptor-2 (HER2).…”

“…These pathways include the type 1 insulin-like growth factor receptor (IGF-1R), mesenchymal-epithelial transition factor receptor (MET receptor), and the human epidermal growth factor receptor-2 (HER2). 26 , 27 Upon activation by their respective ligands, these pathways are able to signal cell effectors downstream of EGFR to stimulation cell proliferation despite the fact that EGFR is not activated. 26 , 27 Current research is focused on quelling these resistance mechanisms in order to restore sensitivity to EGFR inhibition.…”

“… 26 , 27 Upon activation by their respective ligands, these pathways are able to signal cell effectors downstream of EGFR to stimulation cell proliferation despite the fact that EGFR is not activated. 26 , 27 Current research is focused on quelling these resistance mechanisms in order to restore sensitivity to EGFR inhibition.

Figure 1 EGFR Pathways.

…”