Reference Detail

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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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
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
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