Epithelial-mesenchymal transition (EMT) and its role in acquired epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) chemoresistance in non-small cell lung cancer (NSCLC)

Abstract

Epithelial-mesenchymal transition (EMT) is a biological process that involves the transformation of epithelial cells into cells with a mesenchymal phenotype, enhancing their migratory and invasive capabilities. EMT is crucial in embryonic development, tissue healing, and wound repair, and aids in forming diverse cell types and structures. However, aberrant EMT is involved in pathogenic processes, including fibrosis, cancer development, and progression. Recent studies show that EMT contributes to resistance to cancer treatment, including epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) therapy in non-small cell lung cancer (NSCLC). This review discusses the intricate relationship between EMT and acquired chemoresistance to EGFR-TKIs. It details evidence on how EGFR-TKIs might induce EMT and how EMT may cause EGFR-TKI resistance. Understanding these pathways is crucial for developing effective prognostic and therapeutic strategies to predict and combat acquired chemoresistance in NSCLC, advancing the field toward more targeted and personalized treatment approaches.

Keywords: Epidermal growth factor receptor; Epithelial–mesenchymal transition; Non-small cell lung cancer; Resistance; Tyrosine kinase inhibitors.

Graphical abstract

Figure 1

Overview of the major signaling pathways involved in the initiation of epithelial–mesenchymal transition. Epithelial to mesenchymal progression can be induced by several signaling pathways that cooperate to trigger the epithelial–mesenchymal transition program including TGF-β, WNT, Hedgehog, Notch, TNF-α, and tyrosine kinase signaling. Activation of these pathways leads to the expression of transcription factors such as Snail, Slug, Zeb1, and Twist. These factors act by repressing CDH1, which encodes E-cadherin and promotes the expression of mesenchymal markers. AKT: Protein kinase B; CSL: CBF1, suppressor of hairless, lag-1; DVL: Dishevelled segment polarity protein; EGF: Epidermal growth factor; ERK: Extracellular signal-regulated kinase; FGF: Fibroblast growth factor; GLI: Glioma-associated oncogene homolog; Grb2: Growth factor receptor-bound protein 2; GSK3: Glycogen synthase kinase 3; TCF/LEF: T cell factor/lymphoid enhancer factor; IKK: IkappaB kinase; MAM: Mastermind; mTOR: Mammalian target of rapamycin; NICD: Notch intracellular domain; NF-κB: Nuclear factor kappa B; PDGF: Platelet-derived growth factor receptor; PI3K: Phosphoinositide 3-kinase; Ras: Rat sarcoma; RIP: Receptor-interacting protein; RTK: Receptor tyrosine kinase; SoS: Son of sevenless; TGF-β: Transforming growth factor beta; TNF-α: Tumor necrosis factor alpha; TNFR: Tumor necrosis factor alpha receptor; TRAF: TNF receptor-associated factor.

Figure 2

Overview of possible signaling pathways involved in tyrosine kinase inhibitor use-related initiation of epithelial–mesenchymal transition in non-small cell lung cancer. The use of tyrosine kinase inhibitors is linked to abnormal increases in TGF-β levels and greater activation of IGF-1R. These changes in TGF-β and IGF-1R signaling induce epithelial–mesenchymal transition. Additionally, other factors associated with EMT development in in vitro models of acquired gefitinib resistance include the downregulation of specific miRNAs and upregulation of proteins such as TROY, GBP1, and DCLK1. AKT: Protein kinase B; DCLK1: Doublecortin-like kinase 1; ECM: Extracellular matrix; EGF: Epidermal growth factor; EGFR: Epidermal growth factor receptor; EMT: Epithelial–mesenchymal transition, ERK: Extracellular signal-regulated kinase; GBP1: Guanylate binding protein 1; Grb2: Growth factor receptor-bound protein 2; GSK3: Glycogen synthase kinase 3; TCF/LEF: T-cell factor/lymphoid enhancer factor; IGF-1R: Insulin-like growth factor 1 receptor; MEK: Mitogen-activated protein kinase kinase; miRNA: Micro RNA; mTOR: Mammalian target of rapamycin; NF-κB: Nuclear factor kappa B; PI3K: Phosphoinositide 3-kinase; Ras: Rat sarcoma; RTK: Receptor tyrosine kinase; SoS: Son of sevenless; TGF-β: Transforming growth factor beta; TF: Transcription factor.

Figure 3

Overview of possible mechanisms underlying epithelial–mesenchymal transition-related resistance to tyrosine kinase inhibitor therapy in non-small cell lung cancer. Epithelial–mesenchymal transition leads to changes in the levels of various proteins that cause drug resistance. These changes include: (1) increased levels of tyrosine kinases AXL, PDGFR, and FGFR, activating signaling pathways similar to EGFR and creating an alternative survival route for cancer cells; (2) increased levels of triphosphate binding cassette transporters that pump EGFR-TKI drugs out of cancer cells and reduce drug effectiveness; (3) increased levels of PD-L1, inhibiting the immune system's CD8⁺ T cells and allowing the tumor to evade immune attack; (4) decreased levels of BIM, a pro-apoptotic molecule, reducing the cancer cells' tendency to undergo programmed cell death; and (5) increased levels of ALDH1A1, a protein associated with stem cell properties, conferring self-renewal and treatment resistance to cancer cells. ABC: Adenosine triphosphate binding cassette; ADP: Adenosine diphosphate; ALDH1A1: Aldehyde dehydrogenase 1 family, member A1; ATP: Adenosine triphosphate; AXL: Tyrosine-protein kinase receptor UFO; BIM: Bcl-2-like protein 11; CD8⁺: Cluster of differentiation 8; ECM: Extracellular matrix; EGFR: Epidermal growth factor receptor; ERK: Extracellular signal-regulated kinase; FGFR: Fibroblast growth factor receptor; PDGFR: Platelet-derived growth factor receptor; PD-L1: Programmed death-ligand 1; PI3K: Phosphoinositide 3-kinase; TKI: Tyrosine kinase inhibitor.