HSP90 buffers deleterious genetic variations in BRCA1.

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.