Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of all cases. Epidermal growth factor receptor (EGFR) mutations are among the most common oncogenic driver alterations in NSCLC and have led to the development of EGFR-targeted tyrosine kinase inhibitors (TKIs), which have become the standard first-line treatment for patients with EGFR-mutant NSCLC. Although EGFR-TKIs can effectively suppress tumor growth and significantly improve patient outcomes, acquired resistance inevitably develops, resulting in disease progression through diverse molecular mechanisms, including secondary EGFR alterations and co-occurring mutations such as TP53. Therefore, a better understanding of resistance mechanisms and the development of more effective therapeutic strategies remain urgent clinical priorities. The aim of this Research Topic was to highlight recent advances in overcoming EGFR-TKI resistance, including novel therapeutic strategies, emerging resistance mechanisms, predictive biomarkers, and personalized treatment approaches, while providing an overview of current progress and future directions in the field.
EGFR-TKIs remain the standard first-line treatment for patients with EGFR-mutant NSCLC. However, despite their remarkable clinical efficacy, most patients eventually develop disease progression or metastasis due to acquired resistance. Therefore, identifying effective treatment strategies after TKI resistance remains a major clinical challenge.
Zhang et al. evaluated seven treatment regimens for patients with EGFR-mutated advanced NSCLC following TKI progression. The authors found that amivantamab plus lazertinib combined with chemotherapy achieved the longest progression-free survival (PFS) among the seven treatment regimens evaluated, including chemotherapy alone and amivantamab plus chemotherapy. These findings provide valuable evidence for optimizing treatment strategies in patients who develop resistance to first- or second-generation EGFR-TKIs.
Nie et al. reported that patients harboring only EGFR mutations achieved a longer median PFS than those with concurrent TP53 or KRAS mutations during first-line EGFR-TKI treatment. However, following TKI resistance, platinum-based doublet chemotherapy combined with immunotherapy demonstrated greater efficacy in patients with TP53 or KRAS co-mutations, which may be attributable to enhanced tumor immunogenicity and increased sensitivity to immunotherapy.
Zhang et al. investigated the efficacy of immune checkpoint inhibitors (ICIs) in patients with EGFR L858R-mutated NSCLC after TKI failure. The analysis showed that combination ICI-based regimens achieved a higher objective response rate (ORR) and prolonged progression-free survival (PFS), although no significant improvement in overall survival (OS) was observed. These findings suggest that selected patients with EGFR L858R mutations may benefit from combination immunotherapy following TKI resistance.
Ma et al. evaluated the efficacy and safety of antibody-drug conjugates (ADCs) in patients with EGFR-mutant NSCLC after TKI resistance by pooling data from multiple studies. Their analysis demonstrated that ADCs exhibited promising antitumor activity and may represent a potential therapeutic option for overcoming TKI resistance.
Liu et al. compared the effects of early versus delayed radiotherapy in patients with EGFR-mutant NSCLC and brain metastases receiving EGFR-TKIs. The study demonstrated that radiotherapy administered before EGFR-TKI treatment was associated with improved intracranial disease control. In addition, patients harboring EGFR exon 19 deletions experienced more favorable outcomes than those with EGFR exon 21 L858R mutations.
Zhang et al. described the use of serial patient-derived tumor organoid drug sensitivity testing to guide treatment selection after the failure of first-line EGFR-TKI therapy and second-line immunotherapy. The organoid-guided therapeutic strategy resulted in a partial response (PR), highlighting the potential of patient-derived organoids as a promising precision medicine approach for individualized treatment.
Collectively, these studies demonstrate that multiple therapeutic strategies, including combination systemic therapies, radiotherapy optimization, and organoid-guided personalized treatment, offer promising opportunities to improve clinical outcomes after EGFR-TKI resistance.
Acquired resistance remains the central challenge. Eide et al. explored changes in the expression of several immune markers in patients with EGFR mutations after first- and second-line EGFR-TKI treatment. The expression of these markers varied across EGFR mutation subtypes, which may explain differences in the benefits that patients with lung cancer derive from immunotherapy. However, these findings require validation in larger patient cohorts. Wang et al. reported on a patient with metastatic NSCLC harboring an EGFR exon 19 deletion who received an EGFR-TKI as first-line treatment. After several lines of TKI treatment, the mutations persisted despite treatment responses. A novel alteration, an FGFR3-TACC3 fusion, was detected throughout the treatment course. This alteration might have contributed to TKI treatment failure.
EGFR-TKIs are among the most commonly used therapies, but their efficacy remains difficult to predict. Patients may or may not benefit from TKI treatment. Certain biomarkers or clinical factors may correlate with disease progression or overall survival. Shalata et al. retrospectively analyzed variant allele frequency (VAF) in patients with EGFR-mutated NSCLC. A higher VAF, using a cutoff of 30%, predicted longer overall survival and PFS during first-line osimertinib treatment. Guo et al. found that, among patients with advanced lung adenocarcinoma, a low body mass index (<22.1) and/or low fasting insulin levels were associated with a poor prognosis and shorter overall survival. This study identified new clinical risk factors that may influence the outcomes of TKI treatment for lung cancer. Kim et al. evaluated the efficacy of mobocertinib in patients with NSCLC harboring EGFR exon 20 insertion mutations. This EGFR exon 20 inhibitor was associated with a modest improvement in median progression-free survival. In addition, baseline ctDNA findings correlated with favorable outcomes and may serve as a prognostic marker.
This Research Topic also highlighted several novel clinical treatment approaches. Cui et al. described a patient with metastatic lung adenocarcinoma. During treatment with amivantamab plus chemotherapy, the patient developed fever and elevated inflammatory markers but also experienced tumor shrinkage. With adequate supportive care, cytokine release syndrome may be associated with tumor control. Luo et al. focused on a patient with SMARCA4-deficient NSCLC, an aggressive molecular subtype associated with a poor prognosis. The authors used a series of treatment strategies that alleviated superior vena cava syndrome. Treatment with the third-generation EGFR-TKI aumolertinib provided the patient with a period of progression-free survival. Multiple lines of treatment resulted in an overall survival of 2 years. Liu et al. treated a patient with small-cell lung cancer transformed from advanced lung adenocarcinoma with two cycles of olaparib, temozolomide, and atezolizumab, resulting in a partial tumor response. Jin et al. evaluated high-dose furmonertinib in a heavily pretreated patient with advanced EGFR L858R-mutant lung adenocarcinoma and metastases to the liver, bones, and brain. The treatment provided sustained clinical benefit, with recovery of consciousness and improvement in daily functioning.
The articles in this Research Topic addressed the challenges of TKI resistance in lung cancer, potential resistance mechanisms, predictive or prognostic factors, and innovative clinical treatment strategies.
Future precision medicine must focus on optimizing targeted combinations, exploring next-generation antibody-drug conjugates alongside immunotherapy regimens, and defining molecular residual disease. Interdisciplinary collaboration remains essential to translate these preclinical insights into durable, survival-extending clinical practices for patients with advanced lung cancer.
Statements
Author contributions
HL: Conceptualization; Writing – original draft; Writing – review and editing. Y-ZZ: Writing – review and editing. S-ML: Writing – review and editing. S-YL: Writing – review and editing. K-JL: Supervision; Writing – review and editing.
Funding
The author(s) declared that financial support was not received for this work and/or its publication.
Acknowledgments
We thank all authors and readers for their participation in and attention to this Research Topic.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Summary
Keywords
EGFR, lung cancer, precision medicine, resistance, targeted therapy
Citation
Li H, Zheng Y-Z, Liu S-M, Li S-Y and Liu K-J (2026) Editorial: EGFR-targeted therapy in lung cancer: unraveling molecular regulation, overcoming resistance, and advancing precision clinical practice. Front. Mol. Biosci. 13:1936450. doi: 10.3389/fmolb.2026.1936450
Received
13 July 2026
Revised
30 July 2026
Accepted
31 July 2026
Published
10 August 2026
Volume
13 - 2026
Edited and reviewed by
Matteo Becatti, University of Firenze, Italy
Updates
Copyright
© 2026 Li, Zheng, Liu, Li and Liu.
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*Correspondence: Ke-Jun Liu, 15818435527@126.com
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.