Publication

Mutations in the DDR2 Kinase Gene identify a Novel therapeutic target in squamous cell lung cancer

Hammerman, P. S., Sos, M. L., Ramos, A. H., Xu, C., Dutt, A., Zhou, W., Brace, L. E., Woods, B. A., Lin, W., Zhang, J., Deng, X., Lim, S. M., Heynck, S., Peifer, M., Simard, J. R., Lawrence, M. S., Onofrio, R. C., Salvesen, H. B., Seidel, D., Zander, T., Heuckmann, J. M., Soltermann, A., Moch, H., Koker, M., Leenders, F., Gabler, F., Querings, S., Ansen, S., Brambilla, E., Brambilla, C., Lorimier, P., Brustugun, O. T., Helland, A., Petersen, I., Clement, J. H., Groen, H., Timens, W., Sietsma, H., Stoelben, E., Wolf, J., Beer, D. G., Tsao, M. S., Hanna, M., Hatton, C., Eck, M. J., Janne, P. A., Johnson, B. E., Winckler, W., Greulich, H., Bass, A. J., Cho, J., Rauh, D., Gray, N. S., Wong, K-K., Haura, E. B., Thomas, R. K. & Meyerson, M., Jun-2011, In : Cancer discovery. 1, 1, p. 78-89 12 p.

Research output: Contribution to journalArticleAcademicpeer-review

  • Peter S. Hammerman
  • Martin L. Sos
  • Alex H. Ramos
  • Chunxiao Xu
  • Amit Dutt
  • Wenjun Zhou
  • Lear E. Brace
  • Brittany A. Woods
  • Wenchu Lin
  • Jianming Zhang
  • Xianming Deng
  • Sang Min Lim
  • Stefanie Heynck
  • Martin Peifer
  • Jeffrey R. Simard
  • Michael S. Lawrence
  • Robert C. Onofrio
  • Helga B. Salvesen
  • Danila Seidel
  • Thomas Zander
  • Johannes M. Heuckmann
  • Alex Soltermann
  • Holger Moch
  • Mirjam Koker
  • Frauke Leenders
  • Franziska Gabler
  • Silvia Querings
  • Sascha Ansen
  • Elisabeth Brambilla
  • Christian Brambilla
  • Philippe Lorimier
  • Odd Terje Brustugun
  • Aslaug Helland
  • Iver Petersen
  • Joachim H. Clement
  • Harry Groen
  • Wim Timens
  • Hannie Sietsma
  • Erich Stoelben
  • Juergen Wolf
  • David G. Beer
  • Ming Sound Tsao
  • Megan Hanna
  • Charles Hatton
  • Michael J. Eck
  • Pasi A. Janne
  • Bruce E. Johnson
  • Wendy Winckler
  • Heidi Greulich
  • Adam J. Bass
  • Jeonghee Cho
  • Daniel Rauh
  • Nathanael S. Gray
  • Kwok-Kin Wong
  • Eric B. Haura
  • Roman K. Thomas
  • Matthew Meyerson

Although genomically targeted therapies have improved outcomes for patients with lung adenocarcinoma, little is known about the genomic alterations that drive squamous cell cancer (SCC) of the lung. Sanger sequencing of the tyrosine kinome identified mutations in the DDR2 kinase gene in 3.8% of lung SCCs and cell lines. Lung SCC cell lines harboring DDR2 mutations were selectively killed by knockdown of DDR2 by RNA interference or by treatment with the multitargeted kinase inhibitor dasatinib. Tumors established from a DDR2 mutant cell line were sensitive to dasatinib in xenograft models. Expression of mutated DDR2 led to cellular transformation that was blocked by dasatinib. A patient with lung SCC that responded to dasatinib and erlotinib treatment harbored a DDR2 kinase domain mutation. These data suggest that gain-of-function mutations in DDR2 are important oncogenic events and are amenable to therapy with dasatinib. Because dasatinib is already approved for use, these findings could be used to rapidly generate clinical trials.

SIGNIFICANCE: DDR2 mutations are present in 4% of lung SCCs, and DDR2 mutations are associated with sensitivity to dasatinib. These findings provide a rationale for designing clinical trials with the FDA-approved drug dasatinib in patients with lung SCCs. Cancer Discovery; 1(1); 78-89. (C) 2011 AACR.

Original languageEnglish
Pages (from-to)78-89
Number of pages12
JournalCancer discovery
Volume1
Issue number1
Publication statusPublished - Jun-2011

    Keywords

  • DISCOIDIN DOMAIN RECEPTORS, DASATINIB, COLLAGEN, INHIBITOR, PROLIFERATION, ACTIVATION, GEFITINIB, IMATINIB, SRC, IDENTIFICATION

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