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Updated: May 18, 2026
Ultra-Fast Amplicon-Based Next-Generation Sequencing in Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Detection and therapeutic implications of c-Met mutations in small cell lung cancer and neuroendocrine tumors
J Voortman1, T Harada, R P Chang
1National Cancer Institute, Building 10 - Magnuson CC, Room 12N226, 10 Center Drive, Bethesda, MD 20892, USA. giacconeg@mail.nih.gov
Background:
We evaluated the mutation status of c-Met in small cell lung cancer (SCLC) and neuroendocrine tumors (NET), for which relatively limited therapeutic targets have been explored.
Materials And Methods:
c-Met was re-sequenced using cell lines and clinical samples. For in vitro studies, DNA constructs containing a juxtamembrane domain (JMD) and tyrosine kinase domain (TKD) were generated. Detected mutations were introduced into the construct and effects on c-Met phosphorylation and interaction with tyrosine kinase inhibitor drugs BMS777607 and SU11274 were assessed.
Results:
97 specimens were analyzed: 13 SCLC and 2 pulmonary carcinoid cell lines, 46 SCLC and 36 NET clinical specimens. Mutations were only detected in the JMD. No mutations were detected in the TKD. Found mutations consisted of the previously reported R988C and T1010I mutations. One novel JMD mutation, P996S, was detected in a SCLC specimen. The mutation rate in SCLC cell lines was 25% (31% including a derivative cell line), and 6.5% in clinical specimens. The mutation rate in NET was 8.3%. In vitro, there were no differences between wild type, R988C or T1010I mutants regarding c-Met phosphorylation at Y1003, located in the JMD, and at Y1234/1235, located in the TKD. BMS777607 and SU11274 were shown to inhibit phosphorylation of c-Met in wild type and R988C and T1010I mutants in a similar fashion.
Conclusions:
In SCLC and neuroendocrine tumors MET mutations are relatively rare. Detected mutations were located in the juxtamembrane domain and were of no functional relevance as they did not influence c-Met phosphorylation, regardless of TKI treatment.
Insights
MET mutations are rare in small cell lung cancer (SCLC) and neuroendocrine tumors (NET). The identified juxtamembrane domain mutations did not affect c-Met phosphorylation or tyrosine kinase inhibitor efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Limited therapeutic targets exist for small cell lung cancer (SCLC) and neuroendocrine tumors (NET).
- The c-Met receptor tyrosine kinase is a potential therapeutic target in various cancers.
Purpose of the Study:
- To evaluate the mutation status of c-Met in SCLC and NET.
- To determine the functional relevance of identified c-Met mutations.
Main Methods:
- c-Met gene sequencing in SCLC and NET cell lines and clinical specimens.
- In vitro analysis of c-Met phosphorylation and response to tyrosine kinase inhibitors (TKIs) in cells with wild-type and mutant c-Met.
- Generation of DNA constructs with juxtamembrane domain (JMD) and tyrosine kinase domain (TKD) mutations.
Main Results:
- c-Met mutations were detected exclusively in the JMD, not the TKD, in 97 analyzed specimens.
- A novel mutation, P996S, was identified in SCLC, alongside previously reported R988C and T1010I mutations.
- In vitro studies showed no significant differences in c-Met phosphorylation or TKI sensitivity (BMS777607, SU11274) between wild-type and mutant forms.
Conclusions:
- c-Met mutations are infrequent in SCLC and NET.
- The identified JMD mutations lack functional significance, as they do not alter c-Met phosphorylation or TKI response.
- These findings suggest c-Met may not be a primary therapeutic target in these tumor types based on mutation analysis.
