Ddr2 Mutations In Lung Cancer In Adenocarcinoma And Squamous Cell Carcinoma And Association With Met Activation

8115 Background: The discoidin domain receptor tyrosine kinase 2 (DDR2) gene is mutated in a small subset of squamous cell carcinomas (SQCAs) of the lung. Targeting of DDR2 with the inhibitor dasatinib inhibits DDR2-mutated cell line growth and is being investigated in clinical trials for treatment of DDR2-mutated lung tumors. We investigated the frequency and type of DDR2 mutations and their association with other targetable growth factor pathway alterations in non-small cell lung carcinoma (NSCLC). Methods: DNA was extracted from macro-dissected FFPE sections of 105 advanced stage lung carcinomas. Next-generation sequencing was performed using a 36-amplicon panel including the coding regions of DDR2 and exons 11 and 15 of BRAF. DDR2 mutations were confirmed by bidirectional Sanger sequencing. Lung tumors were classified using a standard immunohistochemistry panel. MET pathway activation was assessed with immunohistochemistry using an activation-specific phospho-antibody (pMET, Try1234/1235). MET amplification and ALK rearrangement were assessed using FISH. Mutational analysis for EGFR (exon 18-21), PIK3CA (exons 9 and 20), and KRAS(exons 1-2) was performed using PCR-based DNA sequencing. Results: Heterozygous DDR2 point mutations were identified in 7/105 (6.7%) NSCLCs, including 3/29 (10.3%) SQCAs and 4/69 (5.8%) ACAs, but not in neuroendocrine/large cell carcinomas (0/7). DDR2 mutations were scattered throughout the gene, with 4 present in the discoidin domain and 3 in the kinase domain. MET pathway activation, seen in 25% of DDR2-unmutated cases, was found in 3/6 (50%) DDR2-mutated cases, including 1 SQCA with high-level MET gene amplification. DDR2 mutations were mutually exclusive with BRAF or EGFR mutation or ALK rearrangement, with 1 KRAS-mutated case. Conclusions: DDR2 mutations occur in lung carcinomas with a range of histologic features and in association with MET activation. Dual targeting of the MET and DDR2 kinases in such cases may warrant further investigation.