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Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
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Published on: September 20, 2016

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Somatically mutated ABL1 is an actionable and essential NSCLC survival gene

Ewelina Testoni1, Natalie L Stephenson1, Pedro Torres-Ayuso1

  • 1Signalling Networks in Cancer Group, Cancer Research UK Manchester Institute The University of Manchester, Manchester, UK.

EMBO Molecular Medicine
|January 14, 2016
PubMed

Insights

Targeted therapies for non-small cell lung cancer (NSCLC) are limited by a lack of actionable mutations. This study identifies mutated ABL1 as a dependency in NSCLC, showing ABL1 inhibitors like imatinib are effective against these tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Non-small cell lung cancer (NSCLC) therapy is challenged by a scarcity of actionable mutations.
  • Identifying novel genetic dependencies is crucial for developing targeted treatments for NSCLC.

Purpose of the Study:

  • To identify genetic dependencies in NSCLC.
  • To investigate the role of mutated ABL1 in NSCLC cell survival and response to ABL inhibitors.

Main Methods:

  • Genetic screening to identify NSCLC dependencies.
  • In vitro assays to assess sensitivity to ABL inhibitors.
  • In vivo studies using mouse models of NSCLC.
  • Structural modeling and analysis of ABL1 mutations.

Main Results:

  • Somatically mutated ABL1 was identified as essential for NSCLC cell survival.
  • NSCLC cells with ABL1 mutations showed sensitivity to ABL inhibitors, including imatinib.
  • Imatinib suppressed tumor growth in vivo in NSCLC models with ABL1 gain-of-function mutations.
  • ABL1 mutations increased downstream pathway activation and promoted cytosolic localization, correlating with oncogenic properties.

Conclusions:

  • Mutated ABL1 represents a targetable vulnerability in NSCLC.
  • ABL1 inhibitors, such as imatinib, demonstrate efficacy against NSCLC harboring specific ABL1 mutations.
  • Patients with NSCLC and ABL1 mutations may benefit from stratification for imatinib-based combination therapies.
Keywords:
ABL1 mutationsdasatinibimatinibnon‐small cell lung cancer

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