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The ABL2 kinase regulates an HSF1-dependent transcriptional program required for lung adenocarcinoma brain metastasis

Jacob P Hoj1, Benjamin Mayro1, Ann Marie Pendergast2

  • 1Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710.

Proceedings of the National Academy of Sciences of the United States of America
|December 15, 2020
PubMed

Insights

Researchers discovered a new signaling pathway critical for brain metastasis survival. Targeting the ABL2-HSF1-E2F pathway with specific inhibitors offers a promising therapeutic strategy for brain tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Metastasis Research

Background:

  • Brain metastases are the most frequent intracranial tumors in adults, significantly increasing patient morbidity and mortality.
  • Current therapeutic options for brain metastases are limited, highlighting an urgent need for novel treatment strategies.

Purpose of the Study:

  • To identify and characterize actionable signaling pathways exploited by metastatic tumor cells in the brain.
  • To explore the role of Heat Shock Factor 1 (HSF1) in brain metastasis survival and identify its upstream regulators.

Main Methods:

  • Investigated the role of HSF1 in the survival and outgrowth of metastatic lung cancer cells within the brain.
  • Identified ABL2 tyrosine kinase as an upstream regulator of HSF1 protein expression.
  • Characterized the interaction between ABL2's SH3 domain and HSF1 using biochemical assays and evaluated the effect of pharmacologic inhibitors.

Main Results:

  • HSF1 is essential for the survival and outgrowth of metastatic lung cancer cells in the brain parenchyma.
  • ABL2 tyrosine kinase directly interacts with HSF1 via its SH3 domain at a noncanonical motif.
  • Allosteric inhibitors of ABL2 kinase disrupt the ABL2-HSF1 interaction, impairing HSF1 protein expression and downstream targets.

Conclusions:

  • A novel ABL2-HSF1-E2F signaling pathway is crucial for the survival of brain-metastatic tumor cells.
  • Targeting this pathway, particularly with ABL2 allosteric inhibitors, presents a potential therapeutic strategy for treating brain metastases.
Keywords:
ABL kinasesABL2HSF1brain metastasislung adenocarcinoma

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