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Updated: Nov 28, 2025
Detection of Targetable Alterations in Non-small Cell Lung Cancer using Next-generation Sequencing
Published on: October 10, 2025
Multiplex RNA-based detection of clinically relevant MET alterations in advanced non-small cell lung cancer
Cristina Aguado1, Cristina Teixido2,3, Ruth Román1
1Laboratory of Oncology, Pangaea Oncology, Quirón Dexeus University Hospital, Barcelona, Spain.
Abstract:
MET inhibitors have shown activity in non-small-cell lung cancer patients (NSCLC) with MET amplification and exon 14 skipping (METΔex14). However, patient stratification is imperfect, and thus, response rates have varied widely. Here, we studied MET alterations in 474 advanced NSCLC patients by nCounter, an RNA-based technique, together with next-generation sequencing (NGS), fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and reverse transcriptase polymerase chain reaction (RT-PCR), exploring correlation with clinical benefit. Of the 474 samples analyzed, 422 (89%) yielded valid results by nCounter, which identified 13 patients (3%) with METΔex14 and 15 patients (3.5%) with very-high MET mRNA expression. These two subgroups were mutually exclusive, displayed distinct phenotypes and did not generally coexist with other drivers. For METΔex14, 3/8 (37.5%) samples positive by nCounter tested negative by NGS. Regarding patients with very-high MET mRNA, 92% had MET amplification by FISH and/or NGS. However, FISH failed to identify three patients (30%) with very-high MET RNA expression, among which one received MET tyrosine kinase inhibitor treatment deriving clinical benefit. Our results indicate that quantitative mRNA-based techniques can improve the selection of patients for MET-targeted therapies.
Insights
Quantitative mRNA analysis improves patient selection for MET-targeted therapies in non-small-cell lung cancer (NSCLC). This approach identifies MET exon 14 skipping (METΔex14) and high MET mRNA expression more effectively than other methods.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- MET inhibitors show promise in non-small-cell lung cancer (NSCLC) with MET alterations.
- Current patient stratification methods for MET-targeted therapies are imperfect, leading to variable response rates.
Purpose of the Study:
- To investigate MET alterations in advanced NSCLC patients using various techniques.
- To explore the correlation between MET alterations and clinical benefit from MET-targeted therapies.
- To evaluate the utility of RNA-based nCounter analysis for patient stratification.
Main Methods:
- Analysis of 474 advanced NSCLC patient samples.
- Utilized nCounter (RNA-based), next-generation sequencing (NGS), fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and reverse transcriptase polymerase chain reaction (RT-PCR).
- Compared nCounter results with other molecular diagnostic techniques.
Main Results:
- nCounter identified 13 patients (3%) with MET exon 14 skipping (METΔex14) and 15 patients (3.5%) with very-high MET mRNA expression.
- METΔex14 and very-high MET mRNA expression subgroups were mutually exclusive.
- nCounter detected METΔex14 cases missed by NGS and identified MET amplification in patients where FISH was inconclusive, including one who benefited from treatment.
Conclusions:
- Quantitative mRNA-based techniques, like nCounter, can enhance patient selection for MET-targeted therapies in NSCLC.
- RNA expression analysis offers a valuable complementary approach to traditional methods for detecting MET alterations.
- Improved patient stratification may lead to better clinical outcomes in NSCLC patients treated with MET inhibitors.
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