Pathophysiological mechanisms underlying diarrhea across generations of EGFR-TKIs: The role of ERBB signaling and potential therapies

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), a targeted therapy for the treatment of metastatic non-small cell lung cancer (NSCLC), improve patient outcomes compared to chemotherapy. Nevertheless, EGFR-TKIs are frequently associated with severe gastrointestinal toxicities, particularly diarrheas which often necessitate dose adjustments or treatment interruptions, thereby compromising therapeutic benefits. Current anti-diarrheal treatments are empirical and lack specificity, underscoring the need for a better understanding of the underlying mechanisms. This review highlights 3 key mechanisms underlying EGFR-TKI-induced diarrhea, emphasizing the role of ERBB signaling, including increased chloride secretion, enhanced intestinal epithelial permeability, and alterations in gut microbiota, which collectively contribute to the pathophysiology of diarrheas. The mechanisms contributing to diarrheas are discussed across different EGFR-TKI generations, with attention to their distinct receptor targets and the associated clinical prevalence of diarrheas. Potential therapeutic strategies are also categorized based on these underlying mechanisms, offering insights for effective management of EGFR-TKI-induced diarrheas. • ERBB disruption boosts chloride in all EGFR-TKIs, only 2nd-gen amplifies cAMP-dependent secretion. • Injury-induced ERBB activation limits inflammation and protects cells; EGFR-TKIs disrupt this. • ERBB signaling differs in injury vs recovery; accordingly, 3rd-gen EGFR-TKIs spare epithelial damage. • Regulation of ERBB signaling on gut microbiota & Paneth cells may drive EGFR-TKI effects. • Potential compounds for EGFR-TKIs by mechanism and development stage.