Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metabolism

Background:

• Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with KRAS mutations being a key driver.
• Targeting oncogenic pathways can lead to tumor shrinkage but often results in relapse due to surviving cancer cells.
• The mechanisms by which PDAC cells survive oncogene ablation remain incompletely understood.

Purpose of the Study:

• To investigate the role of mutant KRAS in PDAC maintenance and identify vulnerabilities in surviving tumor cells.
• To explore the metabolic dependencies of dormant PDAC cells that enable relapse after oncogene inhibition.

Main Methods:

• Utilized a novel inducible mouse model of mutated Kras (Kras(G12D)) in a p53(LoxP/WT) background.
• Performed transcriptomic and metabolic analyses on dormant tumor cells surviving oncogene ablation.
• Assessed the sensitivity of surviving cells to oxidative phosphorylation inhibitors.

Main Results:

• A subpopulation of dormant PDAC cells, exhibiting cancer stem cell features, survives oncogene ablation.
• These surviving cells exhibit increased mitochondrial function, autophagy, and lysosome activity, relying on oxidative phosphorylation for energy.
• Surviving cells demonstrate high sensitivity to oxidative phosphorylation inhibitors, which effectively inhibit tumor recurrence.

Conclusions:

• Dormant PDAC cells responsible for relapse depend on oxidative phosphorylation for survival.
• Combined targeting of the KRAS pathway and mitochondrial respiration presents a promising therapeutic strategy for pancreatic cancer.
• Inhibiting oxidative phosphorylation can prevent tumor recurrence in PDAC models.