TY - JOUR
T1 - LKB1 and KEAP1/NRF2 pathways cooperatively promote metabolic reprogramming with enhanced glutamine dependence inKRAS-mutant lung adenocarcinoma
AU - Galan-Cobo, Ana
AU - Sitthideatphaiboon, Piyada
AU - Qu, Xiao
AU - Poteete, Alissa
AU - Pisegna, Marlese A.
AU - Tong, Pan
AU - Chen, Pei Hsuan
AU - Boroughs, Lindsey K.
AU - Rodriguez, Mirna L.M.
AU - Zhang, Winter
AU - Parlati, Francesco
AU - Wang, Jing
AU - Gandhi, Varsha
AU - Skoulidis, Ferdinandos
AU - DeBerardinis, Ralph J.
AU - Minna, John D.
AU - Heymach, John V.
N1 - Publisher Copyright:
©2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85068729869&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-18-3527
DO - 10.1158/0008-5472.CAN-18-3527
M3 - Article
C2 - 31040157
AN - SCOPUS:85068729869
SN - 0008-5472
VL - 79
SP - 3251
EP - 3267
JO - Cancer research
JF - Cancer research
IS - 13
ER -