Format

Send to

Choose Destination
Cancer Res. 2019 Apr 30. pii: canres.3527.2018. doi: 10.1158/0008-5472.CAN-18-3527. [Epub ahead of print]

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

Author information

1
Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center.
2
Department of Medicine, Chulalongkorn University and The King Chulalongkorn Memorial Hospital.
3
Institute of Oncology, Provincial Hospital Affiliated to Shandong University, Shandong University.
4
Thoracic/Head and Neck Medical Oncology, UT MD Anderson Cancer Center.
5
Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center.
6
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center.
7
Medical oncology department, Dana-Farber Cancer Institute.
8
19946 Hibiscus Dr.
9
Research, Calithera Biosciences, Inc.
10
Research, Calithera Biosciences.
11
Experimental Therapeutics, University of Texas MD Anderson Cancer Center.
12
Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center at Dallas.
13
Hamon Center for Therapeutic Oncology Research and Departments of Medicine and Pharmacology, UT Southwestern Medical Center.
14
Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center jheymach@mdanderson.org.

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 co-occurring 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 ROS 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.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center