From EGFR PTM network to TKI resistance: spatial subtypes and targeting in lung cancer.

Lung cancer represents the most prevalent and lethal malignancy worldwide. Although tyrosine kinase inhibitors targeting the epidermal growth factor receptor (EGFR) demonstrate clinical efficacy, the emergence of resistance remains a major therapeutic obstacle. This review comprehensively examines how six key post-translational modifications (PTMs) of EGFR - phosphorylation, palmitoylation, ubiquitination, glycosylation, acetylation, and S-nitrosylation - collectively govern its signaling dynamics, protein turnover, and subcellular trafficking. Based on this mechanistic framework, we propose a novel classification of resistance subtypes: membrane-retained, degradation-evading, nuclear-localized, and mitochondrial-localized EGFR, each defined by distinct PTM signatures and spatial localization. Furthermore, we analyze the intricate crosstalk among these PTMs, revealing hierarchical and often cooperative relationships that ultimately determine the fate and function of EGFR. Our analysis suggests that targeting specific spatial PTM hubs or their interactive networks, rather than EGFR alone, offers a promising strategy to overcome resistance. We also emphasize the need to integrate multi-PTM profiling with spatial proteomics to inform precision combination therapies. This work proposes a shift in the therapeutic paradigm from mere kinase inhibition toward reprogramming the pathological PTM network underlying resistant lung cancer.