Aurora-A drives sorafenib resistance by scaffolding stress granule assembly via phase separation

Lingyu Kong1, Fumei Zhong2,3, Fazhi Yu1

  • 1Department of Digestive disease, The First Affiliated Hospital of University of Science and Technology of China (USTC), State Key Laboratory of Immune Response and Immunotherapy, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, China.

Insights

Aurora-A kinase promotes cancer cell survival by forming stress granules during sorafenib treatment. Disrupting its RNA binding resensitizes cells to this cancer drug.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Biochemistry

Background:

  • Aurora-A kinase is overexpressed in cancers, contributing to tumor progression and therapy resistance.
  • The precise mechanisms linking Aurora-A to drug resistance are not fully understood.

Purpose of the Study:

  • To investigate the role of Aurora-A in sorafenib resistance.
  • To elucidate the molecular mechanisms by which Aurora-A contributes to drug resistance.

Main Methods:

  • Studied the effect of sorafenib treatment on Aurora-A localization and function.
  • Investigated Aurora-A's interaction with RNA and stress granules (SGs).
  • Utilized site-directed mutagenesis to assess the importance of specific Aurora-A residues.

Main Results:

  • Sorafenib treatment induces Aurora-A phase separation and recruitment into stress granules.
  • Aurora-A promotes stress granule assembly, conferring resistance to sorafenib.
  • Aurora-A binds RNA via its intrinsically disordered region (IDR), a process crucial for SG formation and drug resistance.

Conclusions:

  • Aurora-A acts as an RNA-binding scaffold, independent of its kinase activity, to facilitate stress-adaptive biomolecular condensation.
  • Targeting the phase-separation properties of Aurora-A offers a novel therapeutic strategy distinct from inhibiting its kinase signaling.

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