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Brain metastatic outgrowth and osimertinib resistance are potentiated by RhoA in EGFR-mutant lung cancer

Sally J Adua1, Anna Arnal-Estapé1,2, Minghui Zhao1

  • 1Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.

Nature Communications
|December 12, 2022
PubMed

Insights

Drug-resistant lung cancer cells persist in the brain despite treatment with osimertinib. RhoA/SRF signaling and the brain tumor microenvironment promote the growth of these resistant cancer cells.

Area of Science:

  • Oncology
  • Neuroscience
  • Molecular Biology

Background:

  • The brain is a sanctuary site for cancer metastases, often evading systemic therapies.
  • Epidermal Growth Factor Receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) frequently metastasizes to the brain.
  • CNS relapse can occur even with CNS-penetrant therapies like osimertinib.

Purpose of the Study:

  • To investigate the mechanisms linking drug resistance and CNS relapse in EGFR-mutant NSCLC treated with osimertinib.
  • To identify cellular and molecular features that enable cancer cell persistence and proliferation in the brain's microenvironment.

Main Methods:

  • Pre-clinical pharmacological, biological, and molecular studies.
  • In vivo assessment of osimertinib distribution and efficacy.
  • Analysis of the brain microvascular tumor microenvironment (TME).
  • Investigation of RhoA/SRF signaling pathways.

Main Results:

  • Osimertinib, despite widespread distribution, does not eliminate all cancer cells in the brain.
  • The brain TME supports the persistence of osimertinib-resistant cancer cell subpopulations.
  • A Ras homolog family member A (RhoA) and Serum Responsive Factor (SRF) gene expression program regulates this resistant state.
  • RhoA signaling, particularly in response to extracellular laminin in the brain, potentiates tumor cell outgrowth during osimertinib treatment.

Conclusions:

  • Metastatic and drug-resistant cancer cells possess pre-existing and adaptive features that promote brain relapse.
  • RhoA/SRF signaling and the brain TME are critical factors in the evolution of osimertinib-resistant disease.
  • Targeting RhoA/SRF signaling may offer therapeutic strategies against brain metastases in EGFR-mutant NSCLC.

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