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Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer
Peter S Hammerman1, Martin L Sos, Alex H Ramos
1Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA.
Unlabelled:
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.
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.
Insights
Discoveries in squamous cell lung cancer reveal DDR2 kinase gene mutations in 4% of cases. These DDR2 mutations make lung cancer sensitive to dasatinib, a targeted therapy, offering new treatment avenues.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Genomically targeted therapies have improved lung adenocarcinoma outcomes.
- Genomic alterations driving squamous cell lung cancer (SCC) remain largely unknown.
Purpose of the Study:
- To identify genomic alterations driving squamous cell lung cancer.
- To investigate the therapeutic potential of targeting DDR2 mutations in lung SCC.
Main Methods:
- Sanger sequencing of the tyrosine kinome to identify gene mutations.
- RNA interference (RNAi) for DDR2 knock-down.
- Treatment with the multi-targeted kinase inhibitor dasatinib.
- Xenograft models to assess tumor sensitivity to dasatinib.
Main Results:
- Mutations in the DDR2 kinase gene were identified in 3.8% of lung SCCs and cell lines.
- Squamous lung cancer cell lines with DDR2 mutations showed sensitivity to DDR2 knock-down and dasatinib treatment.
- Tumors derived from DDR2 mutant cell lines were sensitive to dasatinib in vivo.
- Expression of mutated DDR2 induced cellular transformation, which was inhibited by dasatinib.
- A patient with lung SCC harboring a DDR2 mutation responded to dasatinib and erlotinib.
Conclusions:
- Gain-of-function mutations in DDR2 are significant oncogenic events in lung SCC.
- DDR2 mutations are associated with sensitivity to dasatinib, an FDA-approved drug.
- These findings support clinical trials of dasatinib for patients with DDR2-mutated lung SCC.
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