Ablation of insulin receptor substrates 1 and 2 suppresses Kras-driven lung tumorigenesis

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metabolism

Background:

• Non-small-cell lung cancer (NSCLC) is a major cause of cancer mortality globally.
• Approximately 25% of NSCLC cases harbor oncogenic Kirsten rat sarcoma (KRAS) mutations.
• The roles of insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) in KRAS-driven lung cancer are not fully understood.

Purpose of the Study:

• To investigate the necessity of insulin/IGF1 signaling, mediated by insulin receptor substrates 1/2 (IRS1/IRS2), in KRAS-mutant lung cancer initiation and progression.
• To identify metabolic vulnerabilities in KRAS-mutant NSCLC upon IR/IGF1R inhibition.

Main Methods:

• Utilized a genetically engineered mouse model of lung cancer with KRAS activation and p53 loss.
• Performed lung-specific dual ablation of Irs1/Irs2 in the mouse model.
• Assessed tumor initiation, survival, Akt activation, and intracellular amino acid levels.
• Inhibited IRS1/IRS2 or IR/IGF1R in human KRAS-mutant NSCLC cells.
• Measured amino acid uptake, intracellular levels, autophagy, and sensitivity to inhibitors.

Main Results:

• Dual ablation of Irs1/Irs2 significantly suppressed tumor initiation and extended survival in the mouse model.
• Tumor cells with Irs1/Irs2 loss exhibited suppressed Akt activation and reduced intracellular amino acids.
• Inhibition of IR/IGF1R in human NSCLC cells decreased amino acid uptake and levels.
• IR/IGF1R inhibition enhanced basal autophagy and increased sensitivity to autophagy and proteasome inhibitors.

Conclusions:

• Insulin/IGF1 signaling is essential for KRAS-mutant lung cancer initiation.
• Reduced amino acid levels represent a metabolic vulnerability in KRAS-mutant NSCLC cells with IR/IGF1R inhibition.
• Combination therapy targeting IR/IGF1R with autophagy or proteasome inhibitors shows promise for treating KRAS-mutant NSCLC.