TSC1 loss synergizes with KRAS activation in lung cancer development in the mouse and confers rapamycin sensitivity

Oncogene. 2010 Mar 18;29(11):1588-97. doi: 10.1038/onc.2009.452. Epub 2009 Dec 7.

Abstract

Germline TSC1 or TSC2 mutations cause tuberous sclerosis complex (TSC), a hamartoma syndrome with lung involvement. To explore the potential interaction between TSC1 and KRAS activation in lung cancer, mice in which Tsc1 loss and Kras(G12D) expression occur in a small fraction of lung epithelial cells were generated. Mice with a combined Tsc1-Kras(G12D) mutation had dramatically reduced tumor latency (median survival: 11.6-15.6 weeks) in comparison with Kras(G12D) alone mutant mice (median survival: 27.5 weeks). Tsc1-Kras(G12D) tumors showed consistent activation of mTOR (mammalian target of rapamycin)C1 and responded to treatment with rapamycin, leading to significantly improved survival, whereas rapamycin had minor effects on cancers in Kras(G12D) alone mice. Loss of heterozygosity for TSC1 or TSC2 was found in 22% of 86 human lung cancer specimens. However, none of the 80 lung cancer lines studied showed evidence of the lack of expression of either TSC1 or TSC2 or a signaling pattern corresponding to complete loss. These data indicate that Tsc1 loss synergizes with the Kras mutation to enhance lung tumorigenesis in the mouse, but that this is a rare event in human lung cancer. Rapamycin may have unique benefit for patients with lung cancer, for whom the TSC1/TSC2 function is limited.

Publication types

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

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / pharmacology
  • Apoptosis
  • Bronchi / drug effects
  • Bronchi / metabolism
  • Bronchi / pathology
  • Cell Line
  • Enzyme Activation
  • Humans
  • Immunoblotting
  • In Situ Nick-End Labeling
  • Kaplan-Meier Estimate
  • Loss of Heterozygosity
  • Lung Neoplasms / genetics
  • Lung Neoplasms / pathology
  • Lung Neoplasms / prevention & control*
  • Mechanistic Target of Rapamycin Complex 1
  • Mice
  • Mice, Knockout
  • Multiprotein Complexes
  • Mutation
  • Proteins
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Sirolimus / pharmacology*
  • TOR Serine-Threonine Kinases
  • Transcription Factors / metabolism
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism

Substances

  • Antibiotics, Antineoplastic
  • Multiprotein Complexes
  • Proteins
  • TSC1 protein, human
  • Transcription Factors
  • Tsc1 protein, mouse
  • Tuberous Sclerosis Complex 1 Protein
  • Tumor Suppressor Proteins
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)
  • Sirolimus