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

Proc Natl Acad Sci U S A. 2018 Apr 17;115(16):4228-4233. doi: 10.1073/pnas.1718414115. Epub 2018 Apr 2.


Non-small-cell lung cancer (NSCLC) is a leading cause of cancer death worldwide, with 25% of cases harboring oncogenic Kirsten rat sarcoma (KRAS). Although KRAS direct binding to and activation of PI3K is required for KRAS-driven lung tumorigenesis, the contribution of insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) in the context of mutant KRAS remains controversial. Here, we provide genetic evidence that lung-specific dual ablation of insulin receptor substrates 1/2 (Irs1/Irs2), which mediate insulin and IGF1 signaling, strongly suppresses tumor initiation and dramatically extends the survival of a mouse model of lung cancer with Kras activation and p53 loss. Mice with Irs1/Irs2 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 IRS1/IRS2 or inhibition of IR/IGF1R in KRAS-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 KRAS-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 KRAS-mutant NSCLC.

Keywords: Kras; amino acids; autophagy; insulin receptor substrates; non–small-cell lung cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Amino Acids / metabolism
  • Animals
  • Autophagy
  • Carcinogenesis / metabolism*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / physiopathology
  • Carcinoma, Non-Small-Cell Lung / prevention & control*
  • Codon, Terminator
  • Genes, ras*
  • Humans
  • Insulin / pharmacology*
  • Insulin Receptor Substrate Proteins / deficiency
  • Insulin Receptor Substrate Proteins / physiology*
  • Insulin-Like Growth Factor I / physiology*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / physiopathology
  • Lung Neoplasms / prevention & control*
  • Mice
  • Neoplasm Proteins / physiology
  • Proteolysis
  • Proto-Oncogene Proteins c-akt / physiology
  • Proto-Oncogene Proteins p21(ras) / physiology*
  • Signal Transduction / physiology


  • Amino Acids
  • Codon, Terminator
  • IGF1 protein, human
  • IRS1 protein, human
  • IRS2 protein, human
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • Irs2 protein, mouse
  • KRAS protein, human
  • Neoplasm Proteins
  • insulin-like growth factor-1, mouse
  • Insulin-Like Growth Factor I
  • Proto-Oncogene Proteins c-akt
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)