Lactate dehydrogenase B is required for the growth of KRAS-dependent lung adenocarcinomas

Mark L. McCleland, Adam S. Adler, Laura Deming, Ely Cosino, Leslie Lee, Elizabeth M. Blackwood, Margaret Solon, Janet Tao, Li Li, David Shames, Erica Jackson, William F. Forrest, Ron Firestein

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Abstract

Purpose: 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. Experimental Design: 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)773-784
Number of pages12
JournalClinical Cancer Research
Volume19
Issue number4
DOIs
Publication statusPublished - 15 Feb 2013
Externally publishedYes

Cite this

McCleland, Mark L. ; Adler, Adam S. ; Deming, Laura ; Cosino, Ely ; Lee, Leslie ; Blackwood, Elizabeth M. ; Solon, Margaret ; Tao, Janet ; Li, Li ; Shames, David ; Jackson, Erica ; Forrest, William F. ; Firestein, Ron. / Lactate dehydrogenase B is required for the growth of KRAS-dependent lung adenocarcinomas. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 4. pp. 773-784.
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abstract = "Purpose: 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. Experimental Design: 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. Conclusion: 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.",
author = "McCleland, {Mark L.} and Adler, {Adam S.} and Laura Deming and Ely Cosino and Leslie Lee and Blackwood, {Elizabeth M.} and Margaret Solon and Janet Tao and Li Li and David Shames and Erica Jackson and Forrest, {William F.} and Ron Firestein",
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McCleland, ML, Adler, AS, Deming, L, Cosino, E, Lee, L, Blackwood, EM, Solon, M, Tao, J, Li, L, Shames, D, Jackson, E, Forrest, WF & Firestein, R 2013, 'Lactate dehydrogenase B is required for the growth of KRAS-dependent lung adenocarcinomas', Clinical Cancer Research, vol. 19, no. 4, pp. 773-784. https://doi.org/10.1158/1078-0432.CCR-12-2638

Lactate dehydrogenase B is required for the growth of KRAS-dependent lung adenocarcinomas. / McCleland, Mark L.; Adler, Adam S.; Deming, Laura; Cosino, Ely; Lee, Leslie; Blackwood, Elizabeth M.; Solon, Margaret; Tao, Janet; Li, Li; Shames, David; Jackson, Erica; Forrest, William F.; Firestein, Ron.

In: Clinical Cancer Research, Vol. 19, No. 4, 15.02.2013, p. 773-784.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Lactate dehydrogenase B is required for the growth of KRAS-dependent lung adenocarcinomas

AU - McCleland, Mark L.

AU - Adler, Adam S.

AU - Deming, Laura

AU - Cosino, Ely

AU - Lee, Leslie

AU - Blackwood, Elizabeth M.

AU - Solon, Margaret

AU - Tao, Janet

AU - Li, Li

AU - Shames, David

AU - Jackson, Erica

AU - Forrest, William F.

AU - Firestein, Ron

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N2 - Purpose: 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. Experimental Design: 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. Conclusion: 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.

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