Elsevier

Journal of Thoracic Oncology

Volume 9, Issue 9, September 2014, Pages 1316-1323
Journal of Thoracic Oncology

Original Articles
RET Mutation and Expression in Small-Cell Lung Cancer

https://doi.org/10.1097/JTO.0000000000000234Get rights and content
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Background

There is growing interest in defining the somatic mutations associated with small-cell lung cancer (SCLC). Unfortunately, a serious blockade to genomic analyses of this disease is a limited access to tumors because surgery is rarely performed. We used our clinical/pathologic database of SCLC patients to determine the availability of biopsy specimens that could be used for genomic studies and to identify tumors for initial oncogene analysis.

Methods

DNA was extracted from six tumors, three primary and three metastatic, and analyzed by SEQUENOM platform technology.

Results

Primary-resected tumor tissue represents less than 3% of all diagnostic specimens in this disease, highlighting the limited access to tissue sufficient for comprehensive genomic analyses. We identified an activating M918T RET somatic mutation in a metastatic SCLC tumor specimen. Bioinformatic search identified RET mutations in other SCLC studies. Stable overexpression of both mutant M918T and wild-type RET in two SCLC cell lines, H1048 and SW1271, activated ERK signaling, MYC expression, and increased cell proliferation, particularly by mutant RET. Stable cells became sensitized to the RET tyrosine kinase inhibitors, vandetanib and ponatinib. Further analysis of RET mRNA expression in SCLC revealed wide variability in both cells and tumors, and SCLC cells demonstrated significantly higher RET expression compared with adenocarcinoma lung cells.

Conclusions

Our data suggest that a subpopulation of SCLC patients may derive benefit from tyrosine kinase inhibitors targeting RET. Coupled with the presence of RET fusion proteins in non-small-cell lung cancer, our data indicate an emerging role for RET in SCLC.

Key Words

RET
Small-cell lung cancer
Oncogene
SNP
Tyrosine kinase inhibitors

Cited by (0)

Supported by grants from the University Hospitals Seidman Cancer Center (AD). This research was also supported by the Tissue Resources Core Facility of the Case Comprehensive Cancer Center (P30 CA043703).

Disclosure: The authors declare no conflicts of interest.