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This is a Literature Review study.

October 15, 2025

Drug Resistance Mechanisms and Strategies of EGFR/ALK Targeted Therapy in Non-Small Cell Lung Cancer

Key Points

Drug resistance mechanisms significantly limit the effectiveness of EGFR and ALK targeted therapies in NSCLC.
Primary resistance includes mutations like EGFR exon 20 insertions and ALK fusion variant heterogeneity.
Current strategies to counteract resistance involve next-generation inhibitors like osimertinib.
Ongoing challenges in treatment include managing complex resistance and toxicity, while future directions aim at enhancing therapeutic innovation.

Abstract

Non-small cell lung cancer (NSCLC) remains a leading cause of global cancer-related mortality. Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) targeted therapies have revolutionized the treatment of patients with corresponding mutations or fusions. However, the emergence of drug resistanceincluding primary resistance (e.g., EGFR exon 20 insertions, ALK fusion variant heterogeneity) and acquired resistance (e.g., EGFR T790M, ALK L1196M mutations)severely limits long-term efficacy. This review systematically synthesizes the molecular mechanisms underlying EGFR/ALK resistance, highlighting both commonalities (e.g., target mutations) and specificities (e.g., small cell transformation in EGFR resistance). It further summarizes current coping strategies, including the development of next-generation inhibitors (osimertinib, lorlatinib), combination therapies (targeted therapy combined with chemotherapy, immunotherapy, or dual-target inhibition), and personalized regimens guided by liquid biopsy. Additionally, the review discusses recent research advances, ongoing challenges (complex resistance, toxicity management), and future directions (single-cell sequencing, multi-target drug design), aiming to provide insights for optimizing clinical practice and accelerating therapeutic innovation in NSCLC.

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