Journal
CANCER DISCOVERY
Volume 9, Issue 9, Pages 1268-1287Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-18-1409
Keywords
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Categories
Funding
- NIH Cancer Center Support Grant [5P30CA045508]
- Cold Spring Harbor Laboratory Association
- V Foundation
- Cold Spring Harbor Laboratory
- Northwell Health Affiliation (Project Lazarus grant)
- NIH [NIH 5P30CA45508, 5P50CA101955, P20CA192996, 1U10CA180944, U01CA224013, U01CA210240-01A1, 1R01CA188134, 1R01CA190092]
- NCI [5F30CA200240]
- Boehringer Ingelheim Fonds Fellowship
- NIH/NCI [RO1 CA200310, RO1 CA216242]
- Medical Research Council UK [MC_UU_00015/3]
- Wellcome Trust Investigator award [110159/Z/15/Z]
- Cancer Research UK [A12077]
- ERC [322842-METABOp53]
- Gates Cambridge Trust
- [R50CA211506]
- MRC [MC_UU_00015/3] Funding Source: UKRI
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Activating KRAS mutations are found in nearly all cases of pancreatic ductal adenocarcinoma (PDAC), yet effective clinical targeting of oncogenic KRAS remains elusive. Understanding of KRAS-dependent PDAC-promoting pathways could lead to the identification of vulnerabilities and the development of new treatments. We show that oncogenic KRAS induces BNIP3L/NIX expression and a selective mitophagy program that restricts glucose flux to the mitochondria and enhances redox capacity. Loss of Nix restores functional mitochondria to cells, increasing demands for NADPH reducing power and decreasing proliferation in glucose-limited conditions. Nix deletion markedly delays progression of pancreatic cancer and improves survival in a murine (KPC) model of PDAC. Although conditional Nix ablation in vivo initially results in the accumulation of mitochondria, mitochondrial content eventually normalizes via increased mitochondrial clearance programs, and pancreatic intraepithelial neoplasia (PanIN) lesions progress to PDAC. We identify the KRAS-NIX mitophagy program as a novel driver of glycolysis, redox robustness, and disease progression in PDAC. SIGNIFICANCE: NIX-mediated mitophagy is a new oncogenic KRAS effector pathway that suppresses functional mitochondrial content to stimulate cell proliferation and augment redox homeostasis. This pathway promotes the progression of PanIN to PDAC and represents a new dependency in pancreatic cancer.
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