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

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 KrasG12D expression occur in a small fraction of lung epithelial cells were generated. Mice with a combined Tsc1-KrasG12D mutation had dramatically reduced tumor latency (median survival: 11.6–15.6 weeks) in comparison with KrasG12D alone mutant mice (median survival: 27.5 weeks). Tsc1-KrasG12D 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 KrasG12D 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.

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Acknowledgements

We thank Kate McNamara and Sara Zaghlul (Dana-Farber Cancer Institute, Boston), Christine Lam, Iza Malinowska-Kolodziej and Mei Zheng (Brigham and Women's Hospital, Boston) for their technical assistance and Roderick T. Bronson (Harvard Medical School, Boston) and Robert Padera and Lucian Chirieac (Brigham and Women's Hospital, Boston) for assistance with pathology review. This study was supported in part by the NIH Grant nos R01 AG2400401 (K-KW), R01 CA122794 (K-KW), K08 AG024004 (K-KW), P01 CA120964 (DJK), the Sidney Kimmel Foundation for Cancer Research (K-KW), the Joan Scarangello Foundation to Conquer Lung Cancer (K-KW and DJK) and the Flight Attendant Medical Research Institute (K-KW).

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Correspondence to D J Kwiatkowski.

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Liang, MC., Ma, J., Chen, L. et al. TSC1 loss synergizes with KRAS activation in lung cancer development in the mouse and confers rapamycin sensitivity. Oncogene 29, 1588–1597 (2010). https://doi.org/10.1038/onc.2009.452

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