LKB1 and KEAP1/NRF2 pathways cooperatively promote metabolic reprogramming with enhanced glutamine dependence inKRAS-mutant lung adenocarcinoma

Ana Galan-Cobo, Piyada Sitthideatphaiboon, Xiao Qu, Alissa Poteete, Marlese A. Pisegna, Pan Tong, Pei Hsuan Chen, Lindsey K. Boroughs, Mirna L.M. Rodriguez, Winter Zhang, Francesco Parlati, Jing Wang, Varsha Gandhi, Ferdinandos Skoulidis, Ralph J. DeBerardinis, John D. Minna, John V. Heymach

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

In KRAS-mutant lung adenocarcinoma, tumors with LKB1 loss (KL) are highly enriched for concurrent KEAP1 mutations, which activate the KEAP1/NRF2 pathway (KLK). Here, we investigated the biological consequences of these cooccurring alterations and explored whether they conferred specific therapeutic vulnerabilities. Compared with KL tumors, KLK tumors exhibited increased expression of genes involved in glutamine metabolism, the tricarboxylic acid cycle, and the redox homeostasis signature. Using isogenic pairs with knockdown or overexpression of LKB1, KEAP1, and NRF2, we found that LKB1 loss results in increased energetic and redox stress marked by increased levels of intracellular reactive oxygen species and decreased levels of ATP, NADPH/NADP+ ratio, and glutathione. Activation of the KEAP1/NRF2 axis in LKB1-deficient cells enhanced cell survival and played a critical role in the maintenance of energetic and redox homeostasis in a glutamine-dependent manner. LKB1 and the KEAP1/NRF2 pathways cooperatively drove metabolic reprogramming and enhanced sensitivity to the glutaminase inhibitor CB-839 in vitro and in vivo. Overall, these findings elucidate the adaptive advantage provided by KEAP1/ NRF2 pathway activation in KL tumors and support clinical testing of glutaminase inhibitor in subsets of KRAS-mutant lung adenocarcinoma.

Original languageEnglish (US)
Pages (from-to)3251-3267
Number of pages17
JournalCancer research
Volume79
Issue number13
DOIs
StatePublished - 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'LKB1 and KEAP1/NRF2 pathways cooperatively promote metabolic reprogramming with enhanced glutamine dependence inKRAS-mutant lung adenocarcinoma'. Together they form a unique fingerprint.

  • Cite this

    Galan-Cobo, A., Sitthideatphaiboon, P., Qu, X., Poteete, A., Pisegna, M. A., Tong, P., Chen, P. H., Boroughs, L. K., Rodriguez, M. L. M., Zhang, W., Parlati, F., Wang, J., Gandhi, V., Skoulidis, F., DeBerardinis, R. J., Minna, J. D., & Heymach, J. V. (2019). LKB1 and KEAP1/NRF2 pathways cooperatively promote metabolic reprogramming with enhanced glutamine dependence inKRAS-mutant lung adenocarcinoma. Cancer research, 79(13), 3251-3267. https://doi.org/10.1158/0008-5472.CAN-18-3527