Mechanisms of Resistance to Targeted Therapy in Epidermal Growth Factor Receptor (EGFR)- and Anaplastic Lymphoma Kinase (ALK)-Mutated Non-small Cell Lung Cancer: Molecular Basis, Emerging Biomarkers, and Therapeutic Strategies.

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.