Tumor-associated macrophages mediate resistance of EGFR-TKIs in non-small cell lung cancer: mechanisms and prospects

Abstract

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the first-line standard treatment for advanced non-small cell lung cancer (NSCLC) with EGFR mutation. However, resistance to EGFR-TKIs is inevitable. Currently, most studies on the mechanism of EGFR-TKIs resistance mainly focus on the spontaneous resistance phenotype of NSCLC cells. Studies have shown that the tumor microenvironment (TME) also mediates EGFR-TKIs resistance in NSCLC. Tumor-associated macrophages (TAMs), one of the central immune cells in the TME of NSCLC, play an essential role in mediating EGFR-TKIs resistance. This study aims to comprehensively review the current mechanisms underlying TAM-mediated resistance to EGFR-TKIs and discuss the potential efficacy of combining EGFR-TKIs with targeted TAMs therapy. Combining EGFR-TKIs with TAMs targeting may improve the prognosis of NSCLC with EGFR mutation to some extent.

Keywords: EGFR-TKIs; NSCLC; exosome; resistance; tumor-associated macrophages.

Figure 1

TAMs mediated EGFR-TKIs resistance through different mechanisms. TAM, tumor-associated macrophage; mTOR, mammalian target of rapamycin; NOS, nitric oxide synthase; EMT, epithelial-mesenchymal transition; RELB, v-rel reticuloendotheliosis viral oncogene homolog B; PD-L1, programmed cell death one ligand 1.

Figure 2

Tumor cells promoted M2-like polarization of TAMs. M2-like TAM: M2-like tumor-associated macrophage; mTOR, mammalian target of rapamycin; lncR SOX2-OT, long non-coding RNA SOX2 overlapping transcript; Smads, drosophila mothers against decapentaplegic proteins.