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

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 were generated in which Tsc1 loss and Kras(G12D) expression occur in a small fraction of lung epithelial cells. Mice with combined Tsc1-Kras(G12D) mutation had dramatically reduced tumor latency (median survival 11.6 – 15.6 weeks) in comparison to Kras(G12D) alone mutant mice (median survival 27.5 weeks). Tsc1-Kras (G12D) tumors showed consistent activation of mTORC1, and responded to treatment with rapamycin leading to significantly improved survival, while 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 80 lung cancer lines studied showed evidence of lack of expression of either TSC1 or TSC2 or a signaling pattern corresponding to complete loss. These data indicate Tsc1 loss synergizes with 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 lung cancer patients in which TSC1/TSC2 function is limited.