Abstract 5147: Lactate transporters are a potential therapeutic target for LKB1-deficient lung cancers
Authors: Guijarro Irene , Poteete Alissa , Tong Pan , Wang Jing , Heymach John 
Published: August 2018

The serine/threonine kinase LKB1 is mutated and inactivated in 20-30% of lung adenocarcinoma representing the second most commonly altered tumor suppressor in non-small cell lung cancer (NSCLC), and to date there are no effective targeting strategies for tumors bearing this mutation. Therefore, new therapeutic approaches are urgently needed for LKB1-deficient tumors. LKB1 activates AMPK, the master sensor of cellular energy and because of this, many of the best known functions of LKB1 are attributed to its ability to control metabolic alterations. Our laboratory and others have demonstrated that loss of LKB1 can promote enhanced glucose metabolism and a shift from aerobic to anaerobic respiration. A result of enhanced glycolysis is an elevated lactate production even under normoxic conditions. It has been reported that lactate-mediated extracellular acidification is a key factor mediating tumor cell invasion and metastasis. We found that LKB1-deficient NSCLC tumors significantly upregulate lactate transporters and, because these tumors exhibit an immunologically inert phenotype, we propose that inhibition of lactate transporters could represent a rational strategy to inhibit tumor growth and enhance immune responses in LKB1 mutant NSCLC. To characterize lactate transporter expression, a panel of NSCLC cell lines was stably transduced to overexpress LKB1 and with shRNA targeting LKB1. We analyzed gene expression of lactate transporters in TCGA dataset of lung adenocarcinoma (LUAD). We validated these results by qPCR and western blot analysis of expression levels of MCT1, MCT4 and MCT14 in human LKB1-intact and deficient cells and in LKB1 KO murine NSCLC cell lines that were generated using CRISPR/Cas9 in a KRASG12D mutant background. To study lactate transporter expression in tumors in vivo, we generated syngeneic NSCLC mouse models via s.c. injection of LKB1-intact and KO murine cells in immunocompetent mice and analyzed the protein expression levels of MCT4 in these tumor samples. The analysis of TCGA LUAD dataset revealed a significant upregulation of lactate transporter SLC16A14 (MCT14) gene expression levels in LKB1-deficient tumors compared with LKB1 wild-type (p&lt;0.001). In vitro, NSCLC LKB1-deficient cells (A549, H460 and H2030) showed increased RNA and protein expression of MCT4 and MCT14 compared to cells where a copy of LKB1 was introduced. In vivo, KRASG12D mutant LKB1 KO tumors from syngeneic mouse models significantly showed an upregulation of MCT4 protein expression compared with KRASG12D mutant LKB1 wild type tumors (p&lt;0.0001). In conclusion, LKB1-deficient NSCLC showed higher levels of glycolysis and significantly elevated expression of lactate transporters in vitro and in vivo compared to LKB1-wild type NSCLC. Additional studies are ongoing to determine the efficacy of lactate transporter inhibition in LKB1-mutant NSCLC.

Citation Format: Irene Guijarro, Alissa Poteete, Pan Tong, Jing Wang, John Heymach. Lactate transporters are a potential therapeutic target for LKB1-deficient lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5147.