Somatically mutated ABL1 is an actionable and essential NSCLC survival gene

Ewelina Testoni, Natalie L Stephenson, Pedro Torres-Ayuso, Anna A Marusiak, Eleanor W Trotter, Andrew Hudson, Cassandra L Hodgkinson, Christopher J Morrow, Caroline Dive, John Brognard

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)105-16
Number of pages12
JournalEMBO Molecular Medicine
Issue number2
Early online date12 Jan 2016
Publication statusPublished - 1 Feb 2016


  • Animals
  • Antineoplastic Agents
  • Carcinoma, Non-Small-Cell Lung
  • Cell Line, Tumor
  • Cell Survival
  • Disease Models, Animal
  • Heterografts
  • Humans
  • Imatinib Mesylate
  • Mice
  • Mutant Proteins
  • Proto-Oncogene Proteins c-abl
  • Treatment Outcome
  • Journal Article
  • Research Support, Non-U.S. Gov't

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre


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