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      Oncogenic and drug sensitive NTRK1 rearrangements in lung cancer

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          Abstract

          We identified novel gene fusions in patients with lung cancer harboring the kinase domain of the NTRK1 gene that encodes the TRKA receptor. Both the MPRIP- NTRK1 and CD74- NTRK1 fusions lead to constitutive TRKA kinase activity and are oncogenic. Treatment of cells expressing NTRK1 fusions with inhibitors of TRKA kinase activity inhibited autophosphorylation of TRKA and cell growth. Three of 91 lung cancer patients (3.3%), without known oncogenic alterations, assayed by NGS or FISH demonstrated evidence of NTRK1 gene fusions.

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          Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer.

          Klarisa Rikova, Ailan Guo, Qingfu Zeng … (2008)
          Despite the success of tyrosine kinase-based cancer therapeutics, for most solid tumors the tyrosine kinases that drive disease remain unknown, limiting our ability to identify drug targets and predict response. Here we present the first large-scale survey of tyrosine kinase activity in lung cancer. Using a phosphoproteomic approach, we characterize tyrosine kinase signaling across 41 non-small cell lung cancer (NSCLC) cell lines and over 150 NSCLC tumors. Profiles of phosphotyrosine signaling are generated and analyzed to identify known oncogenic kinases such as EGFR and c-Met as well as novel ALK and ROS fusion proteins. Other activated tyrosine kinases such as PDGFRalpha and DDR1 not previously implicated in the genesis of NSCLC are also identified. By focusing on activated cell circuitry, the approach outlined here provides insight into cancer biology not available at the chromosomal and transcriptional levels and can be applied broadly across all human cancers.
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            RET, ROS1 and ALK fusions in lung cancer.

            Kengo Takeuchi, Manabu Soda, Yuki Togashi … (2012)
            Through an integrated molecular- and histopathology-based screening system, we performed a screening for fusions of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1, receptor tyrosine kinase (ROS1) in 1,529 lung cancers and identified 44 ALK-fusion-positive and 13 ROS1-fusion-positive adenocarcinomas, including for unidentified fusion partners for ROS1. In addition, we discovered previously unidentified kinase fusions that may be promising for molecular-targeted therapy, kinesin family member 5B (KIF5B)-ret proto-oncogene (RET) and coiled-coil domain containing 6 (CCDC6)-RET, in 14 adenocarcinomas. A multivariate analysis of 1,116 adenocarcinomas containing these 71 kinase-fusion-positive adenocarcinomas identified four independent factors that are indicators of poor prognosis: age ≥ 50 years, male sex, high pathological stage and negative kinase-fusion status.
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              Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer.

              Robert Doebele, Amanda Pilling, Dara L. Aisner … (2012)
              Patients with anaplastic lymphoma kinase (ALK) gene rearrangements often manifest dramatic responses to crizotinib, a small-molecule ALK inhibitor. Unfortunately, not every patient responds and acquired drug resistance inevitably develops in those who do respond. This study aimed to define molecular mechanisms of resistance to crizotinib in patients with ALK(+) non-small cell lung cancer (NSCLC). We analyzed tissue obtained from 14 patients with ALK(+) NSCLC showing evidence of radiologic progression while on crizotinib to define mechanisms of intrinsic and acquired resistance to crizotinib. Eleven patients had material evaluable for molecular analysis. Four patients (36%) developed secondary mutations in the tyrosine kinase domain of ALK. A novel mutation in the ALK domain, encoding a G1269A amino acid substitution that confers resistance to crizotinib in vitro, was identified in two of these cases. Two patients, one with a resistance mutation, exhibited new onset ALK copy number gain (CNG). One patient showed outgrowth of epidermal growth factor receptor (EGFR) mutant NSCLC without evidence of a persistent ALK gene rearrangement. Two patients exhibited a KRAS mutation, one of which occurred without evidence of a persisting ALK gene rearrangement. One patient showed the emergence of an ALK gene fusion-negative tumor compared with the baseline sample but with no identifiable alternate driver. Two patients retained ALK positivity with no identifiable resistance mechanism. Crizotinib resistance in ALK(+) NSCLC occurs through somatic kinase domain mutations, ALK gene fusion CNG, and emergence of separate oncogenic drivers.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 9502015
                Journal ID (pubmed-jr-id): 8791
                Journal ID (nlm-ta): Nat Med
                Journal ID (iso-abbrev): Nat. Med.
                Title: Nature medicine
                ISSN (Print): 1078-8956
                ISSN (Electronic): 1546-170X
                Publication date Nihms-submitted: 29 September 2013
                Publication date (Electronic): 27 October 2013
                Publication date (Print): November 2013
                Publication date PMC-release: 01 May 2014
                Volume: 19
                Issue: 11
                Electronic Location Identifier: 10.1038/nm.3352
                Affiliations
                [1 ]Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO
                [2 ]Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA
                [3 ]University of Colorado Cancer Center, Aurora, CO
                [4 ]Department of Pathology, University of Colorado School of Medicine, Aurora, CO
                [5 ]Department of Thoracic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
                [6 ]Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
                [7 ]Department of Thoracic Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
                [8 ]Broad Institute, Cambridge, MA
                [9 ]Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
                [10 ]Array BioPharma, Boulder, CO
                [11 ]Foundation Medicine, Inc., Boston, MA
                [12 ]Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA
                Author notes
                Corresponding authors: Correspondence to: Robert C. Doebele ( Robert.Doebele@ 123456ucdenver.edu ) or Pasi A. Jänne ( Pasi_Janne@ 123456dfci.harvard.edu )
                Article
                Manuscript ID: NIHMS516390
                DOI: 10.1038/nm.3352
                PMC ID: 3823836
                PubMed ID: 24162815
                SO-VID: 558e20b9-cc8c-4aa1-a44a-dfa41523f3f1
                License:

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: National Cancer Institute : NCI
                Award ID: P50 CA090578 || CA
                Funded by: National Cancer Institute : NCI
                Award ID: P50 CA058187 || CA
                Funded by: National Cancer Institute : NCI
                Award ID: P30 CA046934 || CA
                Categories
                Subject: Article

                ScienceOpen disciplines: Medicine
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                ScienceOpen disciplines: Medicine

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