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HSP90 buffers deleterious genetic variations in BRCA1.

Brant Gracia1, Xing-Han Zhang2, Patricia Montes1

  • 1Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Molecular Cell
|November 20, 2025
PubMed
Summary

Heat shock protein 90 (HSP90) stabilizes mutated BRCA1 proteins, conferring cancer therapy resistance. Inhibiting HSP90 can overcome this resistance, revealing a new therapeutic vulnerability for BRCA1-related cancers.

Keywords:
BRCA1HSP90HSP90 inhibitionPARP inhibitionbreast cancermutational bufferpolytherapyprotein foldingstructural mutationssynthetic lethality

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Area of Science:

  • Molecular Biology
  • Genetics
  • Oncology

Background:

  • Heat shock protein 90 (HSP90) is a molecular chaperone known to buffer genetic variation.
  • The clinical implications of HSP90's buffering role in human diseases, particularly cancer, are not fully understood.

Purpose of the Study:

  • To investigate the role of HSP90 in buffering mutations within the BRCA1 gene, specifically the BRCT domain.
  • To determine the clinical significance of HSP90-buffered BRCA1 mutations in cancer development and therapy resistance.

Main Methods:

  • Analyzing the impact of HSP90 buffering on BRCA1 protein variants with mutations in the BRCT domain.
  • Assessing the functional consequences of these variants on protein stability, partner interactions, and cell survival.
  • Evaluating the effect of HSP90-buffered BRCA1 variants on resistance to poly (ADP-ribose) polymerase (PARP) inhibitors in cancer cells.
  • Investigating the efficacy of low-level HSP90 inhibition in overcoming PARP inhibitor resistance.

Main Results:

  • HSP90 buffers mutations in the BRCA1 BRCT domain, producing variants that maintain protein interactions and stability.
  • These HSP90-buffered BRCA1 variants confer resistance to PARP inhibitors in cancer cells.
  • Targeted inhibition of HSP90 effectively overcomes this resistance, demonstrating a synthetic lethality.
  • HSP90 stabilization of metastable BRCA1 variants reduces clinical disease severity and allows mutations to persist in populations, with an estimated 18% of BRCA1-BRCT missense mutations being buffered.

Conclusions:

  • HSP90 plays a critical role in buffering BRCA1 mutations, impacting cancer predisposition and therapy resistance.
  • Targeting HSP90 presents a novel therapeutic strategy to overcome PARP inhibitor resistance in BRCA1-mutated cancers.
  • This study highlights the clinical significance of HSP90 buffering in a prevalent class of human genetic variations.