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Nature. 2014 Oct 30;514(7524):628-32. doi: 10.1038/nature13611. Epub 2014 Aug 10.

Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function.

Author information

1
1] Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [3].
2
Department of Medicine, Weill Cornell Medical College, New York, New York 10065, USA.
3
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
4
1] Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
5
1] Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [3] Department of Experimental Oncology, European Institute of Oncology, Milan 20139, Italy.
6
Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
7
Pathology Unit, San Raffaele Scientific Institute, Milan 20132, Italy.
8
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
9
Department of Medicine, Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.
10
Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
11
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
12
Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

Abstract

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 PDAC, but targeting mutant KRAS has proved challenging. Targeting oncogene-driven signalling pathways is a clinically validated approach for several devastating diseases. Still, despite marked tumour shrinkage, the frequency of relapse indicates that a fraction of tumour cells survives shut down of oncogenic signalling. Here we explore the role of mutant KRAS in PDAC maintenance using a recently developed inducible mouse model of mutated Kras (Kras(G12D), herein KRas) in a p53(LoxP/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.

PMID:
25119024
PMCID:
PMC4376130
DOI:
10.1038/nature13611
[Indexed for MEDLINE]
Free PMC Article

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