Lactate Dehydrogenase B is required for the growth of KRAS-dependent lung adenocarcinomas
Menée in vitro et in vivo ainsi que sur des échantillons tumoraux prélevés sur des patients atteints d'un adénocarcinome du poumon, cette étude montre que la lactate déshydrogénase B favorise la croissance de tumeurs présentant des mutations du gène KRAS ou des gènes EGFR ou MET
Purpose: This study aims to identify genes within the KRAS genomic amplicon that are both co-upregulated and essential for cell proliferation when KRAS is amplified in lung cancer. Experimental Design: We utilized an integrated genomic approach to identify genes that are co-amplified with KRAS in lung adenocarcinomas and subsequently preformed an RNAi screen to uncover functionally relevant genes. Subsequent functional analysis of a candidate hit from the screen, Lactate Dehydrogenase B (LDHB), was done both in vitro and in vivo by siRNA and 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: Lung adenocarcinomas that harbor KRAS genomic copy number gain and KRAS mutations showed elevated LDHB expression. High LDHB expression was also seen in a smaller proportion of KRAS wildtype lung cancers harboring other oncogenic drivers such as EGFR or MET. Lung adenocarcinomas that exhibited high LDHB expression were uniquely dependent on LDHB for proliferation both in vitro and in xenografted tumors in vivo. Consistent with a role for LDHB in glycolysis and tumor metabolism, KRAS mutant lung adenocarcinomas exhibit an elevated expression of a glycolysis gene signature and are more dependent on glucose for growth. Lastly, 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 growth in a subset of lung adenocarcinoma and may provide a novel therapeutic approach for treating lung cancer.