Redundant kinase activation and resistance of EGFR-tyrosine kinase inhibitors

Abstract

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown dramatic effects against that tumors harboring EGFR activating mutations in the EGFR intracytoplasmic tyrosine kinase domain and resulted in cell apoptosis. Unfortunately, a number of patients ultimately developed resistance by multiple mechanisms. Thus, elucidation of the mechanism of resistance to EGFR-TKIs can provide strategies for blocking or reversing the situation. Recent studies suggested that redundant kinase activation plays pivotal roles in escaping from the effects of EGFR-TKIs. Herein, we aimed to characterize several molecular events involved in the resistance to EGFR-TKIs mediated by redundant kinase activation.

Keywords: EGFR; redundant kinase activation; resistance to EGFR-TKIs.

Figure 1

HER family and EGFR signaling pathway. Ligand-bound receptors form functionally active homodimers or heterodimers, resulting in the activation of downstream signaling pathways such as PI3K/AKT, RAS/RAF/MAPK, PLCγ/PKC and JAK/STAT pathway, leading to cell proliferation, invasion, metastasis, survival and angiogenesis.

Figure 2

Redundant kinase signaling pathway. The activation of redundant kinase leads to downstream pathway such as PI3K/AKT, RAS/RAF/MEK and JAK/STAT signaling actived, which offsets the blockade of EGFR pathway by TKIs.