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

M-C Liang1, J Ma, L Chen

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Oncogene
|December 8, 2009
PubMed

Insights

Tuberous sclerosis complex (TSC) gene mutations interacting with KRAS mutations accelerate lung cancer in mice. Rapamycin treatment improved survival in these mice, suggesting a potential therapy for specific lung cancer patients.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Germline mutations in TSC1 or TSC2 genes cause tuberous sclerosis complex (TSC), a condition associated with hamartomas and lung involvement.
  • KRAS mutations are common drivers in various cancers, including lung cancer.

Purpose of the Study:

  • To investigate the synergistic interaction between Tuberous Sclerosis Complex 1 (TSC1) loss and KRAS activation in lung tumorigenesis.
  • To evaluate the therapeutic potential of rapamycin in lung cancers with combined Tsc1 and Kras mutations.

Main Methods:

  • Generation of genetically engineered mouse models with conditional Tsc1 loss and Kras(G12D) expression in lung epithelial cells.
  • Assessment of tumor latency, survival rates, and molecular signaling pathways (mTORC1).
  • Analysis of human lung cancer specimens and cell lines for TSC1/TSC2 alterations.

Main Results:

  • Combined Tsc1 loss and Kras(G12D) mutation significantly reduced tumor latency and survival in mice compared to Kras(G12D) alone.
  • Tumors with combined mutations showed consistent mTORC1 activation and responded favorably to rapamycin treatment, improving survival.
  • Loss of heterozygosity for TSC1 or TSC2 was observed in 22% of human lung cancer samples, but complete loss was not detected.

Conclusions:

  • Tsc1 loss synergizes with Kras mutations to promote lung tumorigenesis in mice.
  • This genetic interaction appears to be a rare event in human lung cancer.
  • Rapamycin shows promise as a targeted therapy for lung cancer patients with impaired TSC1/TSC2 function.

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