Evolution of an adenocarcinoma in response to selection by targeted kinase inhibitors
| Autor: | Malachi Griffith, David G. Huntsman, Angela Tam, Richard Varhol, Montgomery Martin, Robert A. Holt, Trevor J. Pugh, Nataliya Melnyk, Ryan D. Morin, Jefferson Terry, Tesa M. Severson, Michael Mayo, Timothee Cezard, Yaron S. Butterfield, Martin Hirst, John Yee, Eric Chuah, Steven J.M. Jones, Sohrab P. Shah, Jianghong An, Richard A. Moore, Marco A. Marra, Janessa Laskin, Richard Corbett, Nina Thiessen, Margaret Sutcliffe, Anthony P. Fejes, Thomas Zeng, Inanc Birol, Thomas A. Thomson, Yvonne Y. Li, Yongjun Zhao, Mikhail Bilenky, Obi L. Griffith |
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| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Sorafenib
Niacinamide Indoles Lung Neoplasms Pyridines Gene Dosage Biology Adenocarcinoma medicine.disease_cause Metastasis medicine Sunitinib Humans Pyrroles Selection Genetic Gene Protein Kinase Inhibitors Mutation Massive parallel sequencing Research Phenylurea Compounds Benzenesulfonates Proto-Oncogene Proteins c-ret Cancer High-Throughput Nucleotide Sequencing medicine.disease Neoplasm Proteins Tongue Neoplasms Gene Expression Regulation Neoplastic Cancer research Mitogen-Activated Protein Kinases Proto-Oncogene Proteins c-akt medicine.drug Genes Neoplasm |
| Zdroj: | Genome Biology |
| ISSN: | 1465-6914 1465-6906 |
| Popis: | Background: Adenocarcinomas of the tongue are rare and represent the minority (20 to 25%) of salivary gland tumors affecting the tongue. We investigated the utility of massively parallel sequencing to characterize an adenocarcinoma of the tongue, before and after treatment. Results: In the pre-treatment tumor we identified 7,629 genes within regions of copy number gain. There were 1,078 genes that exhibited increased expression relative to the blood and unrelated tumors and four genes contained somatic protein-coding mutations. Our analysis suggested the tumor cells were driven by the RET oncogene. Genes whose protein products are targeted by the RET inhibitors sunitinib and sorafenib correlated with being amplified and or highly expressed. Consistent with our observations, administration of sunitinib was associated with stable disease lasting 4 months, after which the lung lesions began to grow. Administration of sorafenib and sulindac provided disease stabilization for an additional 3 months after which the cancer progressed and new lesions appeared. A recurring metastasis possessed 7,288 genes within copy number amplicons, 385 genes exhibiting increased expression relative to other tumors and 9 new somatic protein coding mutations. The observed mutations and amplifications were consistent with therapeutic resistance arising through activation of the MAPK and AKT pathways. Conclusions: We conclude that complete genomic characterization of a rare tumor has the potential to aid in clinical decision making and identifying therapeutic approaches where no established treatment protocols exist. These results also provide direct in vivo genomic evidence for mutational evolution within a tumor under drug selection and potential mechanisms of drug resistance accrual. |
| Databáze: | OpenAIRE |
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