Abstract
This study is aimed to identify genes within the KRAS genomic amplicon that are both coupregulated and essential for cell proliferation when KRAS is amplified in lung cancer. We used an integrated genomic approach to identify genes that are coamplified with KRAS in lung adenocarcinomas and subsequently preformed an RNA interference (RNAi) screen to uncover functionally relevant genes. The role of lactate dehydrogenase B (LDHB) was subsequently investigated both in vitro and in vivo by siRNA and short hairpin RNA (shRNA)-mediated knockdown in a panel of lung adenocarcinoma cells lines. LDHB expression was also investigated in patient tumors using microarray and immunohistochemistry analyses. RNAi-mediated depletion of LDHB abrogated cell proliferation both in vitro and in xenografted tumors in vivo. We find that LDHB expression correlates to both KRAS genomic copy number gain and KRAS mutation in lung cancer cell lines and adenocarcinomas. This correlation between LDHB expression and KRAS status is specific for lung cancers and not other tumor types that harbor KRAS mutations. Consistent with a role for LDHB in glycolysis and tumor metabolism, KRAS-mutant lung tumors exhibit elevated expression of a glycolysis gene signature and are more dependent on glycolysis for proliferation compared with KRAS wild-type lung tumors. Finally, high LDHB expression was a significant predictor of shorter survival in patients with lung adenocarcinomas. This study identifies LDHB as a regulator of cell proliferation in a subset of lung adenocarcinoma and may provide a novel therapeutic approach for treating lung cancer.
Highlights
Lung cancer is one of the most prevalent cancer forms, responsible for more than one million annual deaths worldwide
We find that lactate dehydrogenase B (LDHB) expression correlates to both KRAS genomic copy number gain and KRAS mutation in lung cancer cell lines and adenocarcinomas
Genes were selected on the basis of 2 main criteria: (i) they reside within the KRAS amplicon on chromosome 12p and (ii) their gene expression and copy number were significantly upregulated in 10% or more of lung adenocarcinoma tumors and were correlated (P < 0.05; analysis completed with The Cancer Genome Atlas Data Portal; http://tcga-portal.nci.nih.gov)
Summary
Lung cancer is one of the most prevalent cancer forms, responsible for more than one million annual deaths worldwide. Lung cancer is classified according to two main histologic types, small-cell lung cancer (SCLC) and non–small cell lung carcinoma Eighty-five percent of all lung cancers are attributable to NSCLC, of which lung adenocarcinoma is the most frequent histologic subtype [1]. Lung adenocarcinomas frequently harbor mutations in the KRAS oncogene (25%) and the tumor suppressor protein p53. Authors' Affiliations: Departments of 1Pathology, 2Translational Oncology, 3Bioinformatics & Computational Biology, 4Molecular Diagnostics & Cancer Cell Biology, 5Research Oncology, and 6Biostatistics, Genentech, Inc., South San Francisco, California. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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