Bronchial and Peripheral Murine Lung Carcinomas Induced by T790M-L858R Mutant EGFR Respond to HKI-272 and Rapamycin Combination Therapy

Danan Li, Takeshi Shimamura, Hongbin Ji, Liang Chen, Henry J. Haringsma, Kate McNamara, Mei Chih Liang, Samanthi A. Perera, Sara Zaghlul, Christa L. Borgman, Shigeto Kubo, Masaya Takahashi, Yanping Sun, Lucian R. Chirieac, Robert F. Padera, Neal I. Lindeman, Pasi A. Jänne, Roman K. Thomas, Matthew L. Meyerson, Michael J. EckJeffrey A. Engelman, Geoffrey I. Shapiro, Kwok Kin Wong

Research output: Contribution to journalArticle

176 Scopus citations

Abstract

The EGFR T790M mutation has been identified in tumors from lung cancer patients that eventually develop resistance to erlotinib. In this study, we generated a mouse model with doxycycline-inducible expression of a mutant EGFR containing both L858R, an erlotinib-sensitizing mutation, and the T790M resistance mutation (EGFR TL). Expression of EGFR TL led to development of peripheral adenocarcinomas with bronchioloalveolar features in alveoli as well as papillary adenocarcinomas in bronchioles. Treatment with an irreversible EGFR tyrosine kinase inhibitor (TKI), HKI-272, shrunk only peripheral tumors but not bronchial tumors. However, the combination of HKI-272 and rapamycin resulted in significant regression of both types of lung tumors. This combination therapy may potentially benefit lung cancer patients with the EGFR T790M mutation.

Original languageEnglish (US)
Pages (from-to)81-93
Number of pages13
JournalCancer Cell
Volume12
Issue number1
DOIs
StatePublished - Jul 10 2007

Keywords

  • CELLCYCLE
  • CHEMBIO
  • SIGNALING

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Li, D., Shimamura, T., Ji, H., Chen, L., Haringsma, H. J., McNamara, K., Liang, M. C., Perera, S. A., Zaghlul, S., Borgman, C. L., Kubo, S., Takahashi, M., Sun, Y., Chirieac, L. R., Padera, R. F., Lindeman, N. I., Jänne, P. A., Thomas, R. K., Meyerson, M. L., ... Wong, K. K. (2007). Bronchial and Peripheral Murine Lung Carcinomas Induced by T790M-L858R Mutant EGFR Respond to HKI-272 and Rapamycin Combination Therapy. Cancer Cell, 12(1), 81-93. https://doi.org/10.1016/j.ccr.2007.06.005