Authors
Sneha Dhillon, Heena Rathod, Sagar Dhillon
Published in
Cureus. Volume 18. Issue 9. Pages e115685. Epub Sep 02, 2026.
Abstract
Currently, with the spectacular achievement of the tyrosine kinase inhibitors (TKIs), non-small cell lung cancer (NSCLC) carrying mutations of the gene epidermal growth factor receptor (EGFR) and rearrangements of the gene anaplastic lymphoma kinase (ALK) is becoming a paradigm of precision oncology. While there has been great progress in the field of progression-free survival (PFS) and longer-term clinical results have been achieved, resistance sets in, and the long-term impact of these therapies is limited. A summary of the molecular mechanisms of acquired resistance to EGFR- and ALK-targeted drugs is provided here, ranging from secondary changes in the target kinases, via activation of other signaling pathways, to epithelial-mesenchymal transition, intratumoral tumor heterogeneity, and interactions with the tumor microenvironment. For early detection of resistance, emerging biomarkers such as liquid biopsies, circulating tumor DNA, exosomes, and biomarkers, multi-omics characterization and AI-assisted prediction models are discussed. The review also covers an overview of the new treatment strategies on the horizon, including sequential TKI therapy, combination targeted therapy, fourth-generation inhibitors, antibody-drug conjugates, bispecific antibodies, and personalized precision medicine. Finally, current clinical trials, future directions, and challenge/limitations are discussed, focusing on the need for adaptive molecular monitoring and a customized approach to overcome resistance and maximize long-term outcomes in EGFR- and ALK-mutated NSCLC.
PMID:
42829510
Bibliographic data and abstract were imported from PubMed on 04 Oct 2026.
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