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Ref Type Journal Article
PMID (22328973)
Authors Hammerman PS, Sos ML, Ramos AH, Xu C, Dutt A, Zhou W, Brace LE, Woods BA, Lin W, Zhang J, Deng X, Lim SM, Heynck S, Peifer M, Simard JR, Lawrence MS, Onofrio RC, Salvesen HB, Seidel D, Zander T, Heuckmann JM, Soltermann A, Moch H, Koker M, Leenders F, Gabler F, Querings S, Ansén S, Brambilla E, Brambilla C, Lorimier P, Brustugun OT, Helland A, Petersen I, Clement JH, Groen H, Timens W, Sietsma H, Stoelben E, Wolf J, Beer DG, Tsao MS, Hanna M, Hatton C, Eck MJ, Janne PA, Johnson BE, Winckler W, Greulich H, Bass AJ, Cho J, Rauh D, Gray NS, Wong KK, Haura EB, Thomas RK, Meyerson M
Title Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer.
Journal Cancer discovery
Vol 1
Issue 1
Date 2011 Jun
URL
Abstract Text 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.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.

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Gene Name Source Synonyms Protein Domains Gene Description Gene Role
DDR2 NCBI MIG20a|NTRKR3|TKT|TYRO10|WRCN DDR2, discoidin domain receptor tyrosine kinase 2, is a tyrosine kinase receptor activated by collagen, promoting cell migration, proliferation, and survival (PMID: 22328973, PMID: 27398168). Altered expression and mutations of DDR2 have been identified in a variety of solid tumors, including ovarian (PMID: 27398168), lung (PMID: 28161936), gastric (PMID: 27350126), and HNSCC (PMID: 27434411). Oncogene
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
DDR2 G253C missense gain of function - predicted DDR2 G253C lies within the extracellular domain of the Ddr2 protein (UniProt.org). G253C results in transforming activity in cell culture (PMID: 22328973), and therefore, is predicted to result in a gain of Ddr2 protein function.
DDR2 G505S missense gain of function - predicted DDR2 G505S lies within the cytoplasmic domain of the Ddr2 protein (UniProt.org). G505S is transforming in cell culture (PMID: 22328973), and therefore, is predicted to result in a gain of Ddr2 protein function.
DDR2 G774V missense gain of function - predicted DDR2 G774V lies within the protein kinase domain of the Ddr2 protein (PMID: 22328973). G774V is transforming in cell culture (PMID: 22328973), and therefore, is predicted to result in a gain of Ddr2 protein function.
DDR2 I638F missense gain of function DDR2 I638F lies within the protein kinase domain of the Ddr2 protein (UniProt.org). I638F confers a gain of function to the Ddr2 protein, as demonstrated by increased Ddr2 phosphorylation (PMID: 28161936) and Stat5 activation and transformation of cultured cells, and induced tumor formation in mouse xenograft models (PMID: 22328973).
DDR2 L239R missense gain of function - predicted DDR2 L239R lies within the extracellular domain of the Ddr2 protein (UniProt.org). L239R results in transforming activity in cell culture (PMID: 22328973), and therefore, is predicted to result in a gain of Ddr2 protein function.
DDR2 L63V missense gain of function DDR2 L63V lies within the discoidin domain of the Ddr2 protein (PMID: 22328973). L63V confers a gain of function to the Ddr2 protein, as demonstrated by increased Stat5 and Src phosphorylation (PMID: 22328973), elevated phosphorylation of Ddr2, and transformation activity in cell culture (PMID: 28161936).
DDR2 S768R missense gain of function DDR2 S768R lies within the protein kinase domain of the Ddr2 protein (PMID: 22328973). S768R confers a gain of function to the Ddr2 protein, as demonstrated by increased Ddr2 phosphorylation and transforming activity in cultured cells (PMID: 26826182).
DDR2 T654M missense unknown DDR2 T654M lies within the protein kinase domain of the Ddr2 protein (UniProt.org). T654M has been demonstrated to occur as a "gatekeeper" mutation and is associated with secondary drug resistance (PMID: 22328973), but has not been biochemically characterized, and therefore, its effect on Ddr2 protein function is unknown (PubMed, Jul 2020). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
DDR2 I638F Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited growth of transformed cells expressing DDR2 I638F in culture (PMID: 22328973). 22328973
DDR2 L239R Advanced Solid Tumor sensitive Dasatinib Preclinical Actionable In a preclinical study, Sprycel (dasatinib) inhibited growth of transformed cells expressing DDR2 L239R in culture (PMID: 22328973). 22328973
DDR2 G253C Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited growth of transformed cells expressing DDR2 G253C in culture (PMID: 22328973). 22328973
PDGFRA amp lung small cell carcinoma sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited growth of lung squamous cell cancer cells with PDGFRA amplification in culture (PMID: 22328973). 22328973
DDR2 I638F Advanced Solid Tumor sensitive Dasatinib Preclinical Actionable In a preclinical study, Sprycel (dasatinib) inhibited growth of transformed cells expressing DDR2 I638F in culture (PMID: 22328973). 22328973
DDR2 L63V Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited growth of transformed cells expressing DDR2 L63V in culture (PMID: 22328973). 22328973
DDR2 L239R lung squamous cell carcinoma sensitive Dasatinib Preclinical Actionable In a preclinical study, Sprycel (dasatinib) inhibited proliferation of lung squamous cell carcinoma cells harboring a DDR2 L239R mutation in culture (PMID: 22328973). 22328973
DDR2 L239R DDR2 T654M lung squamous cell carcinoma decreased response Dasatinib Preclinical Actionable In a preclinical study, expression of DDR2 T654M in lung squamous cell cancer cells harboring DDR2 L239R resulted in decreased sensitivity to Sprycel (dasatinib) in culture (PMID: 22328973). 22328973
DDR2 S768R lung squamous cell carcinoma predicted - sensitive Dasatinib + Erlotinib Case Reports/Case Series Actionable In a clinical case study, a squamous cell lung cancer patient that demonstrated a radiographic response following Sprycel (dasatinib) and Tarceva (erlotinib) combination treatment was found to carry a DDR2 S768R mutation (PMID: 22328973). 22328973
DDR2 L239R Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited growth of transformed cells expressing DDR2 L239R in culture (PMID: 22328973). 22328973
DDR2 mutant lung squamous cell carcinoma sensitive Dasatinib Preclinical Actionable In a preclinical study, lung squamous cell cancer cells harboring DDR2 mutations demonstrated sensitivity to Sprycel (dasatinib) in culture (PMID: 22328973). 22328973
DDR2 L239R Advanced Solid Tumor sensitive Nilotinib + Saracatinib Preclinical Actionable In a preclinical study, the combination of Saracatinib (AZD0530) and Tasigna (nilotinib) reduced proliferation of transformed cells expressing DDR2 L239R in culture, with increased potency over either agent alone (PMID: 22328973). 22328973
DDR2 L239R lung squamous cell carcinoma sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited growth of lung squamous cell cancer cells harboring DDR2 L239R in culture (PMID: 22328973). 22328973
DDR2 I638F Advanced Solid Tumor sensitive Nilotinib + Saracatinib Preclinical Actionable In a preclinical study, the combination of Saracatinib (AZD0530) and Tasigna (nilotinib) reduced proliferation of transformed cells expressing DDR2 I638F in culture, with increased potency over either agent alone (PMID: 22328973). 22328973
PDGFRA amp lung squamous cell carcinoma sensitive Imatinib Preclinical Actionable In a preclinical study, Gleevec (imatinib) inhibited growth of lung squamous cell cancer cells with PDGFRA amplification in culture (PMID: 22328973). 22328973
DDR2 G505S Advanced Solid Tumor sensitive Dasatinib Preclinical Actionable In a preclinical study, Sprycel (dasatinib) inhibited growth of transformed cells expressing DDR2 G505S in culture (PMID: 22328973). 22328973
DDR2 G505S Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited growth of transformed cells expressing DDR2 G505S in culture (PMID: 22328973). 22328973
DDR2 L63V Advanced Solid Tumor sensitive Nilotinib + Saracatinib Preclinical Actionable In a preclinical study, the combination of Saracatinib (AZD0530) with Tasigna (nilotinib) reduced Src and Stat5 activation and inhibited proliferation of transformed cells expressing DDR2 L63V in culture, with increased potency over either agent alone (PMID: 22328973). 22328973
DDR2 G774V Advanced Solid Tumor sensitive Nilotinib + Saracatinib Preclinical Actionable In a preclinical study, the combination of Saracatinib (AZD0530) and Tasigna (nilotinib) reduced proliferation of transformed cells expressing DDR2 G774V in culture, with increased potency over either agent alone (PMID: 22328973). 22328973
DDR2 I638F lung squamous cell carcinoma sensitive Dasatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Sprycel (dasatinib) inhibited growth of a lung squamous cell carcinoma cell line harboring a DDR2 I638F mutation in culture and in xenograft models (PMID: 22328973). 22328973
PDGFRA amp lung squamous cell carcinoma sensitive Dasatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Sprycel (dasatinib) inhibited growth of a lung squamous cell cancer (SCC) cell line with amplification of PDGFRA in culture, and inhibited tumor growth in PDGFRA-amplified lung SCC xenograft models (PMID: 22328973). 22328973
DDR2 L63V Advanced Solid Tumor sensitive Dasatinib Preclinical Actionable In a preclinical study, Sprycel (dasatinib) inhibited growth of transformed cells expressing DDR2 L63V in culture (PMID: 22328973). 22328973
DDR2 G253C Advanced Solid Tumor sensitive Dasatinib Preclinical Actionable In a preclinical study, Sprycel (dasatinib) inhibited growth of transformed cells expressing DDR2 G253C in culture (PMID: 22328973). 22328973
DDR2 G774V Advanced Solid Tumor sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited growth of transformed cells expressing DDR2 G774V in culture (PMID: 22328973). 22328973
DDR2 I638F lung squamous cell carcinoma sensitive Ponatinib Preclinical Actionable In a preclinical study, Iclusig (ponatinib) inhibited proliferation of lung squamous cell carcinoma cells harboring a DDR2 I638F mutation in cell culture (PMID: 22328973). 22328973
DDR2 G774V Advanced Solid Tumor sensitive Dasatinib Preclinical Actionable In a preclinical study, Sprycel (dasatinib) inhibited growth of transformed cells expressing DDR2 G774V in culture (PMID: 22328973). 22328973
DDR2 G253C Advanced Solid Tumor sensitive Nilotinib + Saracatinib Preclinical Actionable In a preclinical study, the combination of Saracatinib (AZD0530) and Tasigna (nilotinib) reduced proliferation of transformed cells expressing DDR2 G253C in culture, with increased potency over either agent alone (PMID: 22328973). 22328973
DDR2 I638F DDR2 T654M lung squamous cell carcinoma decreased response Dasatinib Preclinical Actionable In a preclinical study, expression of DDR2 T654M in lung squamous cell cancer cells harboring DDR2 I638F resulted in decreased sensitivity to Sprycel (dasatinib) in culture (PMID: 22328973). 22328973
DDR2 L63V lung squamous cell carcinoma sensitive Dasatinib Preclinical Actionable In a preclinical study, Sprycel (dasatinib) prevented colony formation and induced cell death in lung squamous cell carcinoma cells expressing DDR2 L63V in culture (PMID: 22328973). 22328973
DDR2 G505S Advanced Solid Tumor sensitive Nilotinib + Saracatinib Preclinical Actionable In a preclinical study, the combination of Saracatinib (AZD0530) and Tasigna (nilotinib) reduced proliferation of transformed cells expressing DDR2 G505S in culture, with increased potency over either agent alone (PMID: 22328973). 22328973