Mutations in the DDR2 Kinase Gene Identify a Novel Therapeutic Target in Squamous Cell Lung Cancer

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 Ansén, Elisabeth Brambilla, Christian Brambilla, Philippe Lorimier, Odd Terje Brustugun, Åslaug Helland, Iver Petersen, Joachim H. Clement, Harry Groen, Wim Timens, Hannie Sietsma, Erich Stoelben, Jürgen 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

While genomically targeted therapies have improved outcomes for patients with lung adenocarcinoma, little is known about the genomic alterations which drive squamous cell lung cancer. Sanger sequencing of the tyrosine kinome identified mutations in the DDR2 kinase gene in 3.8% of squamous cell lung cancers and cell lines. Squamous lung cancer cell lines harboring DDR2 mutations were selectively killed by knock-down of DDR2 by RNAi or by treatment with the multi-targeted 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 which was blocked by dasatinib. A squamous cell lung cancer patient with a response 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. As dasatinib is already approved for use, these findings could be rapidly translated into clinical trials.