Vertical RAS pathway inhibition in pancreatic cancer drives therapeutically exploitable mitochondrial alterations

Area of Science:

• Oncology
• Metabolic Pathways
• Cancer Therapy

Background:

• Oncogenic KRAS mutations are key drivers of pancreatic ductal adenocarcinoma (PDAC) and its metabolic reprogramming.
• SHP2 is crucial for KRAS activity, and dual SHP2/MAPK inhibition is under clinical investigation for PDAC treatment.
• Therapy resistance in PDAC can arise from exploitable metabolic adaptations.

Purpose of the Study:

• To investigate the metabolic alterations induced by dual SHP2/MEK1/2 inhibition in PDAC.
• To identify vulnerabilities and potential therapeutic strategies to overcome resistance to SHP2/MEK1/2 inhibition in PDAC.

Main Methods:

• Comprehensive analysis of human and murine PDAC cell lines, endogenous tumor models, and patient-derived organoids.
• Assessment of mitochondrial mass and function, ROS homeostasis, lipid peroxidation, anabolic pathways, autophagy, and glycolysis.
• Evaluation of ferroptosis induction via combination therapy and in vivo tumor suppression studies.

Main Results:

• Dual SHP2/MEK1/2 inhibition significantly altered mitochondrial function, ROS homeostasis, and induced lipid peroxidase dependency in PDAC.
• Mitochondrial remodeling persisted into a therapy-resistant state, creating a vulnerability to ferroptosis.
• Combination therapy including SHP2/MEK1/2 inhibition and GPX4 inhibition, or withaferin A, suppressed tumor progression in vivo.

Conclusions:

• Metabolic adaptations, particularly mitochondrial remodeling, are critical in PDAC response to SHP2/MEK1/2 inhibition.
• Targeting ferroptosis in combination with SHP2/MEK1/2 inhibition presents a promising strategy for PDAC treatment, irrespective of molecular subtype.
• This study identifies a metabolic vulnerability that can be leveraged to enhance RAS pathway interference for PDAC therapy.