Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function

Abstract

KRAS mutations are a driver event of pancreatic ductal adenocarcinoma; here, a subpopulation of dormant tumour cells, relying on oxidative phosphorylation for survival, is shown to be responsible for tumour relapse after treatment targeting the KRAS pathway. KRAS mutations represent a driver event of pancreatic ductal adenocarcinoma. Targeting this pathway leads to tumour regression, but the frequency of relapse indicates that a fraction of tumour cells survives even in the absence of oncogenic signalling. Using a Kras/p53 mouse model of pancreatic cancer, in which the expression of oncogenic Kras can be switched off, Giulio Draetta and colleagues show that the subpopulation of dormant tumour cells that survives oncogene ablation and is responsible for tumour relapse is dependent on oxidative phosphorylation (OXPHOS) for survival. These cells show high sensitivity to OXPHOS inhibitors, which can inhibit tumour recurrence, suggesting that combined targeting of the KRAS pathway and mitochondrial respiration might be effective in the treatment of pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in western countries, with a median survival of 6 months and an extremely low percentage of long-term surviving patients. KRAS mutations are known to be a driver event of PDAC1, but targeting mutant KRAS has proved challenging2. Targeting oncogene-driven signalling pathways is a clinically validated approach for several devastating diseases3,4. Still, despite marked tumour shrinkage, the frequency of relapse indicates that a fraction of tumour cells survives shut down of oncogenic signalling5,6. Here we explore the role of mutant KRAS in PDAC maintenance using a recently developed inducible mouse model of mutated Kras1 (KrasG12D, herein KRas) in a p53LoxP/WT background. We demonstrate that a subpopulation of dormant tumour cells surviving oncogene ablation (surviving cells) and responsible for tumour relapse has features of cancer stem cells and relies on oxidative phosphorylation for survival. Transcriptomic and metabolic analyses of surviving cells reveal prominent expression of genes governing mitochondrial function, autophagy and lysosome activity, as well as a strong reliance on mitochondrial respiration and a decreased dependence on glycolysis for cellular energetics. Accordingly, surviving cells show high sensitivity to oxidative phosphorylation inhibitors, which can inhibit tumour recurrence. Our integrated analyses illuminate a therapeutic strategy of combined targeting of the KRAS pathway and mitochondrial respiration to manage pancreatic cancer.