SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo

Nat Med. 2018 Jul;24(7):961-967. doi: 10.1038/s41591-018-0023-9. Epub 2018 May 28.


RAS mutations are frequent in human cancer, especially in pancreatic, colorectal and non-small-cell lung cancers (NSCLCs)1-3. Inhibition of the RAS oncoproteins has proven difficult4, and attempts to target downstream effectors5-7 have been hampered by the activation of compensatory resistance mechanisms8. It is also well established that KRAS-mutant tumors are insensitive to inhibition of upstream growth factor receptor signaling. Thus, epidermal growth factor receptor antibody therapy is only effective in KRAS wild-type colon cancers9,10. Consistently, inhibition of SHP2 (also known as PTPN11), which links receptor tyrosine kinase signaling to the RAS-RAF-MEK-ERK pathway11,12, was shown to be ineffective in KRAS-mutant or BRAF-mutant cancer cell lines13. Our data also indicate that SHP2 inhibition in KRAS-mutant NSCLC cells under normal cell culture conditions has little effect. By contrast, SHP2 inhibition under growth factor-limiting conditions in vitro results in a senescence response. In vivo, inhibition of SHP2 in KRAS-mutant NSCLC also provokes a senescence response, which is exacerbated by MEK inhibition. Our data identify SHP2 inhibition as an unexpected vulnerability of KRAS-mutant NSCLC cells that remains undetected in cell culture and can be exploited therapeutically.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Non-Small-Cell Lung / genetics*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cellular Senescence / drug effects
  • Guanosine Triphosphate / metabolism
  • Humans
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / pathology
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Mutation / genetics*
  • Protein Kinase Inhibitors / pharmacology
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism*
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Xenograft Model Antitumor Assays


  • KRAS protein, human
  • Protein Kinase Inhibitors
  • Guanosine Triphosphate
  • Mitogen-Activated Protein Kinase Kinases
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Proto-Oncogene Proteins p21(ras)