Ablation of insulin receptor substrates 1 and 2 suppresses <i>Kras</i>-driven lung tumorigenesis.

Abstract

Non-small-cell lung cancer (NSCLC) is a leading cause of cancer death worldwide, with 25% of cases harboring oncogenic Kirsten rat sarcoma (<i>KRAS</i>). Although KRAS direct binding to and activation of PI3K is required for <i>KRAS</i>-driven lung tumorigenesis, the contribution of insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) in the context of mutant <i>KRAS</i> remains controversial. Here, we provide genetic evidence that lung-specific dual ablation of insulin receptor substrates 1/2 (<i>Irs1</i>/<i>Irs2</i>), which mediate insulin and IGF1 signaling, strongly suppresses tumor initiation and dramatically extends the survival of a mouse model of lung cancer with <i>Kras</i> activation and <i>p53</i> loss. Mice with <i>Irs1</i>/<i>Irs2</i> loss eventually succumb to tumor burden, with tumor cells displaying suppressed Akt activation and strikingly diminished intracellular levels of essential amino acids. Acute loss of <i>IRS1</i>/<i>IRS2</i> or inhibition of IR/IGF1R in <i>KRAS</i>-mutant human NSCLC cells decreases the uptake and lowers the intracellular levels of amino acids, while enhancing basal autophagy and sensitivity to autophagy and proteasome inhibitors. These findings demonstrate that insulin/IGF1 signaling is required for <i>KRAS</i>-mutant lung cancer initiation, and identify decreased amino acid levels as a metabolic vulnerability in tumor cells with IR/IGF1R inhibition. Consequently, combinatorial targeting of IR/IGF1R with autophagy or proteasome inhibitors may represent an effective therapeutic strategy in <i>KRAS</i>-mutant NSCLC.