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Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
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SMARCA4-inactivating mutations increase sensitivity to Aurora kinase A inhibitor VX-680 in non-small cell lung

Vural Tagal1, Shuguang Wei1, Wei Zhang2,3

  • 1Department of Biochemistry, UT Southwestern, Dallas, Texas 75390, USA.

Nature Communications
|January 20, 2017
PubMed

Insights

Non-small cell lung cancer (NSCLC) cells with SMARCA4/BRG1 loss depend on AURKA activity. Inhibiting AURKA causes cell death, offering a potential therapeutic strategy for NSCLC patients with these specific mutations.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • SMARCA4/BRG1 mutations leading to protein loss are common in non-small cell lung cancer (NSCLC).
  • A synthetic lethal therapeutic approach for SMARCA4/BRG1-deficient NSCLC remains elusive.
  • Identifying vulnerabilities in these cancer cells is crucial for developing targeted treatments.

Purpose of the Study:

  • To investigate potential therapeutic targets in NSCLC cells with SMARCA4/BRG1 loss.
  • To determine if AURKA (Aurora Kinase A) activity is essential for the survival of these cancer cells.
  • To explore the role of DLGAP5 (Discs Large Homologue-Associated Protein 5) in the context of SMARCA4/BRG1 deficiency.

Main Methods:

  • RNA interference (RNAi) to deplete AURKA.
  • Chemical inhibition of AURKA.
  • In vitro cell death assays.
  • In vivo xenograft mouse models.
  • Analysis of DLGAP5's role in mitotic spindle assembly.

Main Results:

  • AURKA activity was found to be essential in NSCLC cells lacking functional SMARCA4/BRG1.
  • RNAi-mediated depletion or chemical inhibition of AURKA induced apoptosis and cell death in these cells.
  • DLGAP5, crucial for AURKA-dependent spindle assembly, was vital for the survival of SMARCA4/BRG1 mutant cells but not wild-type cells.

Conclusions:

  • AURKA is a critical vulnerability in NSCLC cells with SMARCA4/BRG1-inactivating mutations.
  • AURKA inhibitors represent a promising therapeutic strategy for a subset of NSCLC patients.
  • Biomarker-driven clinical studies targeting AURKA could be beneficial for treating SMARCA4/BRG1-mutant NSCLCs.

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