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Berlin Brandenburg

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  • 1
    Language: English
    In: Science translational medicine, 14 June 2017, Vol.9(394)
    Description: Oncogenic fusion events have been identified in a broad range of tumors. Among them, rearrangements represent distinct and potentially druggable targets that are recurrently found in lung adenocarcinomas. We provide further evidence that current anti-RET drugs may not be potent enough to induce durable responses in such tumors. We report that potent inhibitors, such as AD80 or ponatinib, that stably bind in the DFG-out conformation of RET may overcome these limitations and selectively kill -rearranged tumors. Using chemical genomics in conjunction with phosphoproteomic analyses in -rearranged cells, we identify the CCDC6-RET mutation and drug-induced mitogen-activated protein kinase pathway reactivation as possible mechanisms by which tumors may escape the activity of RET inhibitors. Our data provide mechanistic insight into the druggability of RET kinase fusions that may be of help for the development of effective therapies targeting such tumors.
    Keywords: Adenocarcinoma -- Metabolism ; Gene Rearrangement -- Genetics ; Lung Neoplasms -- Metabolism ; Protein Kinase Inhibitors -- Pharmacology ; Proto-Oncogene Proteins C-Ret -- Genetics
    ISSN: 19466234
    E-ISSN: 1946-6242
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  • 2
    Language: English
    In: Science translational medicine, 15 December 2010, Vol.2(62), pp.62ra93
    Description: Lung cancer remains one of the leading causes of cancer-related death in developed countries. Although lung adenocarcinomas with EGFR mutations or EML4-ALK fusions respond to treatment by epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibition, respectively, squamous cell lung cancer currently lacks therapeutically exploitable genetic alterations. We conducted a systematic search in a set of 232 lung cancer specimens for genetic alterations that were therapeutically amenable and then performed high-resolution gene copy number analyses. We identified frequent and focal fibroblast growth factor receptor 1 (FGFR1) amplification in squamous cell lung cancer (n = 155), but not in other lung cancer subtypes, and, by fluorescence in situ hybridization, confirmed the presence of FGFR1 amplifications in an independent cohort of squamous cell lung cancer samples (22% of cases). Using cell-based screening with the FGFR inhibitor PD173074 in a large (n = 83) panel of lung cancer cell lines, we demonstrated that this compound inhibited growth and induced apoptosis specifically in those lung cancer cells carrying amplified FGFR1. We validated the FGFR1 dependence of FGFR1-amplified cell lines by FGFR1 knockdown and by ectopic expression of an FGFR1-resistant allele (FGFR1(V561M)), which rescued FGFR1-amplified cells from PD173074-mediated cytotoxicity. Finally, we showed that inhibition of FGFR1 with a small molecule led to significant tumor shrinkage in vivo. Thus, focal FGFR1 amplification is common in squamous cell lung cancer and associated with tumor growth and survival, suggesting that FGFR inhibitors may be a viable therapeutic option in this cohort of patients.
    Keywords: Lung Neoplasms -- Genetics ; Receptor, Fibroblast Growth Factor, Type 1 -- Metabolism
    ISSN: 19466234
    E-ISSN: 1946-6242
    Library Location Call Number Volume/Issue/Year Availability
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