Metabolic rewiring in mutant Kras lung cancer

Abstract

Lung cancer is the leading cause of cancer-related death worldwide, reflecting an unfortunate combination of very high prevalence and low survival rates, as most cases are diagnosed at advanced stages when treatment efficacy is limited. Lung cancer comprises several disease groups with non small cell lung cancer (NSCLC) accounting for ~ 85% of cases and lung adenocarcinoma being its most frequent histological subtype. Mutations in Kirsten rat sarcoma viral oncogene homologue (KRAS) affect ~ 30% of lung adenocarcinomas but unlike other commonly altered proteins (EGFR and ALK, affected in ~ 14% and 7% of cases respectively), mutant KRAS remains untargetable. Therapeutic strategies that rely instead on the inhibition of mutant KRAS functional output or the targeting of mutant KRAS cellular dependencies (i.e. synthetic lethality) are an appealing alternative approach. Recent studies focused on the metabolic properties of mutant KRAS lung tumours have uncovered unique metabolic features that can potentially be exploited therapeutically. We review these findings here with a particular focus on in vivo, physiologic, mutant KRAS activity.

Keywords: lung cancer; metabolism; mouse models; mutant Kras; therapy.

Figure 1. Human NSCLC metabolism based on in situ glucose flux analysis.

Representation of glucose-derived carbon flux in human NSCLC following ¹³C-glucose infusion [23, 27, 28]. Metabolites referred to in the main text (*), as well as others discussed in the references are indicated. Enhanced glucose metabolism (orange) and alternative pathway fuels (purple) are shown. PDH, pyruvate dehydrogenase; PC, pyruvate carboxylase.

Figure 2. Metabolic rewiring in lung tumours from Kras^G12D/+; p53^-/- mice.

Schematic representation of metabolic networks in lung tumours from Kras^G12D/+;p53^-/- mice based on in vivo flux/tracing analyses. Enhanced flux from different labelled substrates is shown as indicated, with orange depicting glucose metabolism (based on ¹³C-Glucose [21, 57]); green: amino acid metabolism (¹³C-Leucine/Valine; solid), ¹⁵N-Leucine; dashed [25]); and purple: fatty acid metabolism (²H₂O [62]). Grey arrow depicts similar flux relative to normal tissue [57]. Slc2a1, Glucose transporter 1; Acc, Acetyl-Co A carboxylase; Gcs, glutamylcysteine synthetase; Pdh, pyruvate dehydrogenase; Pc, pyruvate carboxylase.

Figure 3. Metabolic reprogramming during mutant Kras-driven lung tumour progression.

Representation of cellular phenotypes altered during the progression of low (adenoma, Grade I and II adenocarcinoma) to high grade (Grade III and IV adenocarcinoma) lung tumours in Kras^G12D/+;p53^-/- mice.

Figure 4. Metabolic targets of mutant Kras lung tumours validated in vivo.

Schematic representation of metabolic targeting strategies that showed therapeutic efficacy in spontaneous mutant Kras lung tumours (GEMM KO and/or pharmacologic inhibition (*)) or NSCLC cell line xenografts. Metabolites and enzymes are shown, with genes overexpressed in human NSCLC samples indicated in red. Targeting approach and method of inhibition are shown in blue. ETC: Electron Transport Chain; 2DG: 2-deoxyglucose; BSO: Buthionine Sulfoximine; GEMM KO: Genetically engineered mouse model knock-out; CRISPR KO: Clustered regularly interspaced short palindromic repeats knock-out; shRNA: short-hairpin RNA; SMI: Small molecule inhibitor.