Abstract
BackgroundAdvanced non-small cell lung cancer (NSCLC) is an aggressive tumor that is treated with a combination of chemotherapy and radiation if the patient is not a candidate for surgery. Predictive biomarkers for response to radiotherapy are lacking in this patient population, making it a non-tailored therapy regimen with unknown outcome. Twenty to 30 % of NSCLC harbor an activating mutation in KRAS that may confer radioresistance. We hypothesized that mutant KRAS can regulate glutamine metabolism genes in NSCLC and maintain tumor redox balance through transamination reactions that generate cytosolic NADPH via malic enzyme 1 (ME1), which may contribute to radioresistance.FindingsA doxycycline-inducible mouse model of KRASG12D driven NSCLC and patient data was analyzed from multiple publicly accessible databases including TCGA, CCLE, NCBI GEO and Project Achilles. ME1 expression was found to be mutant KRAS associated in both a NSCLC mouse model and human NSCLC cancer cell lines. Perturbing glutamine metabolism sensitized mutant KRAS, but not wild-type KRAS NSCLC cell lines to radiation treatment. NSCLC survival analysis revealed that patients with elevated ME1 and GOT1 expression had significantly worse outcomes after radiotherapy, but this was not seen after chemotherapy alone.ConclusionsKRAS driven glutamine metabolism genes, specifically ME1 and GOT1 reactions, may be a predictive marker and potential therapeutic target for radiotherapy in NSCLC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13014-015-0457-x) contains supplementary material, which is available to authorized users.
Highlights
Advanced non-small cell lung cancer (NSCLC) is an aggressive tumor that is treated with a combination of chemotherapy and radiation if the patient is not a candidate for surgery
We found that KRASG12D induction upregulated malic enzyme 1 (ME1) and GOT1 mRNA in mouse doxycycline inducible KRASG12D embryonic fibroblasts derived from the transgenic mice (Fig. 1c, Additional file 1: Figure S1B)
Our analyses indicate that mutant KRAS is associated with ME1 gene expression in NSCLC and that ME1 is an essential viability gene in mutant, but not wild-type, KRAS cell lines
Summary
This multi-database translational study is the first to identify mutant KRAS associated glutamine metabolism genes, GOT1 and ME1, as potential radioresistance biomarkers in NSCLC. ~93 % of patients with a complete response to IR treatment harbored wild-type KRAS in their tumors To explain these observations, we hypothesize that KRAS-reprogrammed glutamine flux through GOT1 and ME1 is critical to maintain cytosolic NADPH levels for redox balance and lipid synthesis in NSCLC. In the face of ROS stress, as observed with IR treatment, NADPH is preferentially used to maintain reduced glutathione and thioredoxin 1 to protect cells from ROS damage [19]. In this context, KRAS may reprogram NSCLC glutamine metabolism similar to that observed in pancreatic cancer to maintain redox balance, providing an oncogene driven mechanism of radioresistance. While there are currently no known specific inhibitors of ME1 or GOT1, targeting upstream glutamine utilization via glutaminase 1 (GLS1, Fig. 1a) inhibition (with BPTES or CB-839) may blunt downstream utilization of glutamine/glutamate through GOT1 and ME1, depleting tumor, but not normal tissue, NADPH/GSH production, leading to tumor-specific radiosensitivity while sparing normal tissue [24]
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