Induction of Lung Tumors and Mutational Analysis in FVB/N Mice Treated with the Tobacco Carcinogen 4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone

Identification of a Highly Effective Rapamycin Schedule that Markedly Reduces the Size, Multiplicity, and Phenotypic Progression of Tobacco Carcinogen–Induced Murine Lung Tumors

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-06-2570 ◽

2007 ◽

Vol 13 (7) ◽

pp. 2281-2289 ◽

Cited By ~ 61

Author(s):

Courtney A. Granville ◽

Noel Warfel ◽

Junji Tsurutani ◽

M. Christine Hollander ◽

Matthew Robertson ◽

...

Keyword(s):

Lung Tumors ◽

Murine Lung ◽

Tobacco Carcinogen ◽

Highly Effective

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Club cells form lung adenocarcinomas and maintain the alveoli of adult mice

eLife ◽

10.7554/elife.45571 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 9

Author(s):

Magda Spella ◽

Ioannis Lilis ◽

Mario AA Pepe ◽

Yuanyuan Chen ◽

Maria Armaka ◽

...

Keyword(s):

Lung Diseases ◽

Lung Tumors ◽

Alveolar Cells ◽

Kras Mutations ◽

Alveolar Epithelial ◽

Adult Mice ◽

Chronic Lung Diseases ◽

Tobacco Carcinogen ◽

Club Cells ◽

Genetic Labeling

Lung cancer and chronic lung diseases impose major disease burdens worldwide and are caused by inhaled noxious agents including tobacco smoke. The cellular origins of environmental-induced lung tumors and of the dysfunctional airway and alveolar epithelial turnover observed with chronic lung diseases are unknown. To address this, we combined mouse models of genetic labeling and ablation of airway (club) and alveolar cells with exposure to environmental noxious and carcinogenic agents. Club cells are shown to survive KRAS mutations and to form lung tumors after tobacco carcinogen exposure. Increasing numbers of club cells are found in the alveoli with aging and after lung injury, but go undetected since they express alveolar proteins. Ablation of club cells prevents chemical lung tumors and causes alveolar destruction in adult mice. Hence club cells are important in alveolar maintenance and carcinogenesis and may be a therapeutic target against premalignancy and chronic lung disease.

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Mutational analysis of theHER2 gene in lung tumors from Caucasian patients: Mutations are mainly present in adenocarcinomas with bronchioloalveolar features

International Journal of Cancer ◽

10.1002/ijc.22143 ◽

2006 ◽

Vol 119 (11) ◽

pp. 2586-2591 ◽

Cited By ~ 116

Author(s):

Fiamma Buttitta ◽

Fabio Barassi ◽

Giuseppina Fresu ◽

Lara Felicioni ◽

Antonio Chella ◽

...

Keyword(s):

Mutational Analysis ◽

Lung Tumors ◽

Caucasian Patients

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DDR2 mutations in lung cancer in adenocarcinoma and squamous cell carcinoma and association with MET activation.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.8115 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 8115-8115

Author(s):

Justin P Windham ◽

Yongbao Wang ◽

Rebecca A Hilferty ◽

Marc A Sanidad ◽

Daniel Jones

Keyword(s):

Squamous Cell ◽

Mutational Analysis ◽

Small Cell Lung Carcinoma ◽

Lung Tumors ◽

Small Subset ◽

Alk Rearrangement ◽

Cell Lung Carcinoma ◽

Lung Carcinomas ◽

Tyrosine Kinase 2 ◽

Pathway 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.

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