Letters to Nature

Nature 410, 1111-1116 (26 April 2001) | doi:10.1038/35074129; Received 14 November 2000; Accepted 23 January 2001

Somatic activation of the K-ras oncogene causes early onset lung cancer in mice

Leisa Johnson1,2, Kim Mercer1,3, Doron Greenbaum1,4, Roderick T. Bronson5, Denise Crowley1,3, David A. Tuveson1,3,6 & Tyler Jacks1,3

  1. Department of Biology, Massachusetts Institute of Technology, and
  2. Howard Hughes Medical Institute, Center for Cancer Research, Cambridge, Massachusetts 02139, USA
  3. Department of Pathology, Tufts University Schools of Medicine and Veterinary Medicine, Boston, Massachusetts 02111, USA
  4. Dana-Farber Cancer Institute, Division of Adult Oncology, Boston, Massachusetts 02115, USA
  5. Present address: Onyx Pharmaceuticals, Richmond, California 94806, USA
  6. Present address: Department of Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, California 94143, USA.

Correspondence to: Tyler Jacks1,3 Correspondence and requests for materials should be addressed to T.J. (e-mail: Email: tjacks@mit.edu).

About 30% of human tumours carry ras gene mutations1, 2. Of the three genes in this family (composed of K-ras, N-ras and H-ras), K-ras is the most frequently mutated member in human tumours, including adenocarcinomas of the pancreas (approx70–90% incidence), colon (approx50%) and lung (approx25–50%)1, 2, 3, 4, 5, 6. To constuct mouse tumour models involving K-ras, we used a new gene targeting procedure to create mouse strains carrying oncogenic alleles of K-ras that can be activated only on a spontaneous recombination event in the whole animal. Here we show that mice carrying these mutations were highly predisposed to a range of tumour types, predominantly early onset lung cancer. This model was further characterized by examining the effects of germline mutations in the tumour suppressor gene p53, which is known to be mutated along with K-ras in human tumours. This approach has several advantages over traditional transgenic strategies, including that it more closely recapitulates spontaneous oncogene activation as seen in human cancers.