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Ann Oncol ; 28(3): 597-603, 2017 03 01.
Article in English | MEDLINE | ID: mdl-27998968

ABSTRACT

Background: Lung cancer is the leading cause of cancer-related deaths across the world. In this study, we present therapeutically relevant genetic alterations in lung adenocarcinoma of Indian origin. Materials and methods: Forty-five primary lung adenocarcinoma tumors were sequenced for 676 amplicons using RainDance cancer panel at an average coverage of 1500 × (reads per million mapped reads). To validate the findings, 49 mutations across 23 genes were genotyped in an additional set of 363 primary lung adenocarcinoma tumors using mass spectrometry. NIH/3T3 cells over expressing mutant and wild-type FGFR3 constructs were characterized for anchorage independent growth, constitutive activation, tumor formation and sensitivity to FGFR inhibitors using in vitro and xenograft mouse models. Results: We present the first spectrum of actionable alterations in lung adenocarcinoma tumors of Indian origin, and shows that mutations of FGFR3 are present in 20 of 363 (5.5%) patients. These FGFR3 mutations are constitutively active and oncogenic when ectopically expressed in NIH/3T3 cells and using a xenograft model in NOD/SCID mice. Inhibition of FGFR3 kinase activity inhibits transformation of NIH/3T3 overexpressing FGFR3 constructs and growth of tumors driven by FGFR3 in the xenograft models. The reduction in tumor size in the mouse is paralleled by a reduction in the amounts of phospho-ERK, validating the in vitro findings. Interestingly, the FGFR3 mutations are significantly higher in a proportion of younger patients and show a trend toward better overall survival, compared with patients lacking actionable alterations or those harboring KRAS mutations. Conclusion: We present the first actionable mutation spectrum in Indian lung cancer genome. These findings implicate FGFR3 as a novel therapeutic in lung adenocarcinoma.


Subject(s)
Adenocarcinoma/drug therapy , Adenocarcinoma/genetics , Drug Resistance, Neoplasm/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Receptor, Fibroblast Growth Factor, Type 3/genetics , Adenocarcinoma/pathology , Adenocarcinoma of Lung , Adult , Aged , Animals , Cell Proliferation/drug effects , Female , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/pathology , Male , Mice , Middle Aged , Mutation , NIH 3T3 Cells , Proto-Oncogene Proteins p21(ras)/genetics , Pyrimidines/administration & dosage , Receptor, Fibroblast Growth Factor, Type 3/antagonists & inhibitors , Xenograft Model Antitumor Assays
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