Mutations in the DDR2 kinase gene identify a novel therapeutic target in squamous cell lung cancer.
نویسندگان
چکیده
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.
منابع مشابه
A new target for therapy in squamous cell carcinoma of the lung.
Investigators report the identification of novel somatic mutations in the DDR2 kinase gene in squamous cell carcinoma of the lung. Cellular, biochemical, and human data suggest that tumor cells harboring DDR2 mutations have increased sensitivity to existing tyrosine kinase inhibitors, providing rationale for clinical trials of agents that inhibit DDR2 kinase in the disease.
متن کاملPrevalence of Mutations in Discoidin Domain-Containing Receptor Tyrosine Kinase 2 (DDR2) in Squamous Cell Lung Cancers in Korean Patients
PURPOSE The discoidin domain-containing receptor tyrosine kinase 2 (DDR2) is known to contain mutations in a small subset of patients with squamous cell carcinomas (SCC) of the lung. Studying the DDR2 mutations in patients with SCC of the lung would advance our understanding and guide the development of therapeutic strategies against lung cancer. MATERIALS AND METHODS We selected 100 samples ...
متن کاملSensitive methods for detection of the S768R substitution in exon 18 of the DDR2 gene in patients with central nervous system metastases of non-small cell lung cancer
Discoidin death receptor 2 (DDR2) receptor belongs to a DDR family that shows a tyrosine kinase activity. The somatic mutations in DDR2 gene, reported in non-small cell lung cancer (NSCLC), are involved in up-regulation of cells' migration, proliferation and survival. A S768R substitution in DDR2 gene was commonly reported in squamous cell lung carcinoma. Clinical data of patients carrying the ...
متن کاملA review of the role of dopamine receptors and novel therapeutic strategies in non-small cell lung cancer (NSCLC)
Lung cancer is a very aggressive and most deadly cancer in both men and women. Lung cancer is divided into two types of small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC is divided into 3 subgroups: adenocarcinoma (AC), squamous cell carcinoma (SqCC) and large cell carcinoma (LCC). Dopamine is involved in controlling motions, cognition, emotions, memory and reward mech...
متن کاملDetection of Mutations in Exons 5 and 8 of Tumor Suppressor Tp53 Gene in Patients with Squamous Cell Carcinoma of Lung Hospitalized in Afzalipour Hospital, Kerman, Iran
Introduction: Despite improvements in the diagnosis and treatment of lung cancer in the past two decades, it has remained the most common cause of death from cancer worldwide. Among all genes that are mutated in lung cancer, TP53 located on chromosome 17P13/1 has a significant diagnostic and prognostic value. TP53 mutations have been extensively studied in lung cancer and TP53 mutational spectr...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Cancer discovery
دوره 1 1 شماره
صفحات -
تاریخ انتشار 2011