Inflammatory signaling in targeted therapy resistance: focus on EGFR-targeted treatment

Mechanisms of resistance to targeted therapy mediated by inflammatory signals and immune cells. (A) Resistance mechanism induced by upregulation of TNF and IFN in EGFR-targeted therapy. TNF is rapidly activated in response to EGFR inhibition and plays a crucial role in resistance to EGFR-targeted treatments. Upon TNF binding to TNFR1, IKK is recruited and activated by the TNFR1 complex. The activated IKK phosphorylates IκB, which is then rapidly degraded by polyubiquitination. The degradation of IκB releases NF-κB, allowing NF-κB to translocate into the nucleus and promote the transcription of numerous NF-κB target genes. Nuclear NF-κB binds to the promoter of TNF, increasing TNF expression in a feed-forward loop. Many of these NF-κB target genes have anti-apoptotic and pro-survival functions. Additionally, type I interferon (IFN-I) is upregulated in response to EGFR inhibition. RIG-I is strongly induced by EGFR inhibition, leading to the ubiquitous expression and activation of TBK1. The ubiquitin ligase, TRIM32, associates with TBK1 upon EGFR inhibition and is necessary for K63-linked ubiquitination and TBK1 activation. Inhibiting mutant EGFR triggers IFN-I upregulation via the RIG-I-TBK1-IRF3 pathway. STAT1 activation by IFN-I promotes cell survival and therapeutic resistance in the context of EGFR inhibition. (B) Immune cells or inflammatory factors in the TME resist targeted therapy in various ways. BRAF inhibitors (BRAFi) paradoxically activate the mitogen-activated protein kinase (MAPK) pathway in macrophages in BRAF-mutant melanomas, leading to the production of VEGF, which reactivates the MAPK pathway in melanoma cells and promotes cell growth. Additionally, inflammatory factors released from dying tumor and immune cells during targeted therapy may activate novel survival pathways in tumor cells, contributing to resistance to targeted therapy. TKIs, tyrosine kinase inhibitors; TNF, tumor necrosis factor; EGFR, epidermal growth factor receptor; TNFR1, tumor necrosis factor receptor 1; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; IκB, inhibitor of NF-κB alpha; IKK, IκB kinase; IFN, interferon; RIG-I, retinoic acid-inducible gene I; TBK1, TANK-binding kinase 1; TRIM32; tripartite motif-containing 32; IRF3, interferon regulatory factor 3; STAT1, signal transducer and activator of transcription 1; VEGF, vascular endothelial growth factor; TME, tumor microenvironment.