title: Lactate dehydrogenase B is required for the growth of KRAS-dependent lung adenocarcinomas.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pathology, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: Mark L
authors.initials: ML
authors.lastname: McCleland
authors.forename: Adam S
authors.initials: AS
authors.lastname: Adler
authors.forename: Laura
authors.initials: L
authors.lastname: Deming
authors.forename: Ely
authors.initials: E
authors.lastname: Cosino
authors.forename: Leslie
authors.initials: L
authors.lastname: Lee
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Blackwood
authors.forename: Margaret
authors.initials: M
authors.lastname: Solon
authors.forename: Janet
authors.initials: J
authors.lastname: Tao
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: David
authors.initials: D
authors.lastname: Shames
authors.forename: Erica
authors.initials: E
authors.lastname: Jackson
authors.forename: William F
authors.initials: WF
authors.lastname: Forrest
authors.forename: Ron
authors.initials: R
authors.lastname: Firestein
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D007770:L-Lactate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D034741:RNA, Small Interfering; D014183:Transplantation, Heterologous; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D007527:Isoenzymes; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D007770:L-Lactate Dehydrogenase; C409667:lactate dehydrogenase 1; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins