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Adaptive responses to dasatinib-treated lung squamous cell cancer cells harboring DDR2 mutations.
Bai, Yun; Kim, Jae-Young; Watters, January M; Fang, Bin; Kinose, Fumi; Song, Lanxi; Koomen, John M; Teer, Jamie K; Fisher, Kate; Chen, Yian Ann; Rix, Uwe; Haura, Eric B.
Afiliação
  • Bai Y; Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612.
  • Kim JY; Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612.
  • Watters JM; Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612.
  • Fang B; Proteomics Core Facility, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612.
  • Kinose F; Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612.
  • Song L; Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612.
  • Koomen JM; Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612.
  • Teer JK; Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612.
  • Fisher K; Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612.
  • Chen YA; Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612.
  • Rix U; Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612.
  • Haura EB; Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612.
Cancer Res ; 74(24): 7217-7228, 2014 Dec 15.
Article em En | MEDLINE | ID: mdl-25348954
DDR2 mutations occur in approximately 4% of lung squamous cell cancer (SCC) where the tyrosine kinase inhibitor dasatinib has emerged as a new therapeutic option. We found that ERK and AKT phosphorylation was weakly inhibited by dasatinib in DDR2-mutant lung SCC cells, suggesting that dasatinib inhibits survival signals distinct from other oncogenic receptor tyrosine kinases (RTK) and/or compensatory signals exist that dampen dasatinib activity. To gain better insight into dasatinib's action in these cells, we assessed altered global tyrosine phosphorylation (pY) after dasatinib exposure using a mass spectrometry-based quantitative phosphoproteomics approach. Overlaying protein-protein interaction relationships upon this dasatinib-regulated pY network revealed decreased phosphorylation of Src family kinases and their targets. Conversely, dasatinib enhanced tyrosine phosphorylation in a panel of RTK and their signaling adaptor complexes, including EGFR, MET/GAB1, and IGF1R/IRS2, implicating a RTK-driven adaptive response associated with dasatinib. To address the significance of this observation, these results were further integrated with results from a small-molecule chemical library screen. We found that dasatinib combined with MET and insulin-like growth factor receptor (IGF1R) inhibitors had a synergistic effect, and ligand stimulation of EGFR and MET rescued DDR2-mutant lung SCC cells from dasatinib-induced loss of cell viability. Importantly, we observed high levels of tyrosine-phosphorylated EGFR and MET in a panel of human lung SCC tissues harboring DDR2 mutations. Our results highlight potential RTK-driven adaptive-resistant mechanisms upon DDR2 targeting, and they suggest new, rationale cotargeting strategies for DDR2-mutant lung SCC.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pirimidinas / Tiazóis / Receptores Mitogênicos / Receptores Proteína Tirosina Quinases / Neoplasias de Células Escamosas / Neoplasias Pulmonares Limite: Humans Idioma: En Ano de publicação: 2014 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pirimidinas / Tiazóis / Receptores Mitogênicos / Receptores Proteína Tirosina Quinases / Neoplasias de Células Escamosas / Neoplasias Pulmonares Limite: Humans Idioma: En Ano de publicação: 2014 Tipo de documento: Article