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    Somatically mutated ABL1 is an actionable and essential NSCLC survival gene.

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    Authors
    Testoni, Ewelina
    Stephenson, Natalie L
    Torres-Ayuso, Pedro
    Marusiak, Anna A
    Trotter, Eleanor W
    Hudson, Andrew M
    Hodgkinson, Cassandra L
    Morrow, Christopher J
    Dive, Caroline
    Brognard, John
    Affiliation
    Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute
    Issue Date
    2016-01-12
    
    Metadata
    Show full item record
    Abstract
    The lack of actionable mutations in patients with non-small cell lung cancer (NSCLC) presents a significant hurdle in the design of targeted therapies for this disease. Here, we identify somatically mutated ABL1 as a genetic dependency that is required to maintain NSCLC cell survival. We demonstrate that NSCLC cells with ABL1 mutations are sensitive to ABL inhibitors and we verify that the drug-induced effects on cell viability are specific to pharmacological inhibition of the ABL1 kinase. Furthermore, we confirm that imatinib suppresses lung tumor growth in vivo, specifically in lung cancer cells harboring a gain-of-function (GOF) mutation in ABL1. Consistent with structural modeling, we demonstrate that mutations in ABL1 identified in primary NSCLC tumors and a lung cancer cell line increase downstream pathway activation compared to wild-type ABL1. Finally, we observe that the ABL1 cancer mutants display an increased cytosolic localization, which is associated with the oncogenic properties of the ABL1 kinase. In summary, our results suggest that NSCLC patients with ABL1 mutations could be stratified for treatment with imatinib in combination with other therapies.
    Citation
    Somatically mutated ABL1 is an actionable and essential NSCLC survival gene. 2016: EMBO Mol Med
    Journal
    EMBO Molecular Medicine
    URI
    http://hdl.handle.net/10541/596641
    DOI
    10.15252/emmm.201505456
    PubMed ID
    26758680
    Type
    Article
    Language
    en
    ISSN
    1757-4684
    ae974a485f413a2113503eed53cd6c53
    10.15252/emmm.201505456
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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