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Detection of Targetable Alterations in Non-small Cell Lung Cancer using Next-generation Sequencing
Published on: October 10, 2025
Beyond EGFR and ALK inhibition: unravelling and exploiting novel genetic alterations in advanced non small-cell lung
Raffaele Califano1, Aidalena Abidin2, Noor-Ul-Ain Tariq2
1Cancer Research UK Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, United Kingdom; Department of Medical Oncology, University Hospital of South Manchester Foundation Trust, Manchester M23 9LT, United Kingdom.
Abstract:
During the last decade, thoracic oncology has witnessed an unprecedented outburst of knowledge regarding molecular biology of non small-cell lung cancer (NSCLC). The implementation of high-throughput sequencing analysis and genomic technologies has led to the identification of novel molecular events that characterize NSCLC transformation and may represent critical oncogenic drivers amenable to targeted therapy. Among these, the presence of activating mutations of the epidermal growth factor receptor (EGFR) gene and of chromosomic rearrangements in the anaplastic-lymphoma kinase (ALK) proto-oncogene, have been the first well characterized genetic alterations with corresponding targeted agents to enter the clinical arena. Nevertheless, in the recent years a number of other oncogenic drivers beyond EGFR and ALK inhibition have emerged as novel molecular targets with potential therapeutic implications, including mutations in the genes KRAS, BRAF, HER2, PI3KCA and DDR2, as well as ROS1 and RET rearrangements and MET, HER2 and FGFR1 gene amplifications. The aim of this review is to provide comprehensive information on the novel therapeutic targets identified by recent preclinical evidence and to discuss developments in molecular treatments targeting these oncogenic drivers or actionable mutations beyond EGFR and ALK in advanced NSCLC.
Insights
Discover novel molecular targets beyond EGFR and ALK for advanced non-small cell lung cancer (NSCLC). This review details emerging oncogenic drivers and targeted therapies for improved NSCLC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Thoracic oncology has advanced significantly due to molecular biology insights in non-small cell lung cancer (NSCLC).
- High-throughput sequencing has identified key molecular events driving NSCLC transformation and potential therapeutic targets.
- Epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements were early targets for NSCLC therapy.
Purpose of the Study:
- To review novel therapeutic targets in advanced NSCLC beyond EGFR and ALK.
- To discuss emerging oncogenic drivers and actionable mutations identified through preclinical research.
- To explore developments in molecular treatments for these newly identified targets.
Main Methods:
- Comprehensive literature review of recent preclinical evidence.
- Analysis of genomic technologies and high-throughput sequencing data.
- Synthesis of information on emerging molecular targets and their therapeutic implications.
Main Results:
- Identification of multiple novel oncogenic drivers in NSCLC, including KRAS, BRAF, HER2, PI3KCA, DDR2 mutations, and ROS1, RET, MET, FGFR1 alterations.
- Preclinical data supports these novel targets for potential therapeutic intervention.
- These findings expand the landscape of targeted therapy options for advanced NSCLC.
Conclusions:
- Emerging molecular targets beyond EGFR and ALK offer new avenues for advanced NSCLC treatment.
- Targeted therapies addressing these novel drivers hold significant therapeutic potential.
- Continued research into molecular alterations is crucial for advancing personalized NSCLC medicine.
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