Tumor necrosis factor (TNF) and Epidermal growth factor receptor (EGFR) (TNF, EGFR)

Tumor necrosis factor (TNF) and epidermal growth factor receptor (EGFR) are two distinct molecular targets that function within highly interconnected signaling pathways, particularly in the context of oncogenesis and therapeutic resistance [4, 5]. TNF is a potent proinflammatory cytokine primarily involved in systemic inflammation and the regulation of immune cells, but it also activates the NF-kappaB pathway, which can promote cell survival [12, 13]. EGFR is a transmembrane receptor tyrosine kinase that plays a pivotal role in cell growth, proliferation, and differentiation, and is frequently mutated or overexpressed in various cancers such as non-small cell lung cancer (NSCLC) [2, 15]. Clinical and preclinical studies have identified an 'EGFR/TNF axis' where EGFR inhibition triggers a TNF-driven adaptive response, allowing cancer cells to bypass growth factor dependence and survive through inflammatory signaling [4, 5, 11]. Consequently, the simultaneous targeting of both proteins—using combination therapies such as EGFR tyrosine kinase inhibitors and TNF-neutralizing biologics—is being investigated to overcome resistance in NSCLC and glioblastoma [1, 2, 6]. This dual-targeting strategy aims to enhance treatment efficacy by blocking both the primary oncogenic driver and its secondary escape route [4, 5].

Other names

TNF-alphaTumor necrosis factor-alphaCachectinErbB-1HER1Epidermal growth factor receptorTumor necrosis factor

Dual inhibition involves blocking the EGFR tyrosine kinase or ligand binding to suppress primary oncogenic growth signals, while simultaneously neutralizing the cytokine TNF to prevent the activation of the NF-kappaB bypass pathway, which otherwise confers resistance to EGFR-targeted therapies [4, 5].