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Review
. 2025 Apr 15:18:2151-2171.
doi: 10.2147/IJGM.S512395. eCollection 2025.

Mechanisms of Resistance to ALK Inhibitors and Corresponding Treatment Strategies in Lung Cancer

Jiajun Xie #  1 , Yinghao Gao #  2 , Weiguo Xu  1 , Jing Zhu  1
Affiliations
Review

Mechanisms of Resistance to ALK Inhibitors and Corresponding Treatment Strategies in Lung Cancer

Jiajun Xie et al. Int J Gen Med. .

Abstract

Lung cancer continues to be a leading cause of cancer-related mortality and morbidity worldwide. The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene accounts for approximately 3%-5% of gene mutation types. Targeted therapies for ALK mutations have made significant advancements in recent decades, enabling a considerable number of patients to achieve the goal of five-year survival benefits. However, overcoming the drug resistance that arises with current ALK tyrosine kinase inhibitors (TKIs) remain a major challenge in ALK-targeted therapies. In this review, we briefly discuss the primary and secondary mechanisms of resistance to ALK-TKIs, and explore treatment strategies based on progressive resistance models. Meanwhile, novel drugs and combination therapies are being actively researched and developed to address these challenges. The aim is to offer new insights into the mechanisms of resistance and the corresponding treatment strategies to ALK inhibitors.

Keywords: ALK-TKIs; EML4-ALK; lung cancer; resistance mechanism; treatment strategies.

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Conflict of interest statement

The authors declare no conflicts of interest in this work.

Figures

Figure 1
Figure 1
EML4-ALK signaling pathway.
Figure 2
Figure 2
EML4-ALK fusion gene structure.
Figure 3
Figure 3
Secondary gene mutations to ALK-TKIs.
Figure 4
Figure 4
Summary of treatment strategies for drug resistance.
See this image and copyright information in PMC

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