Heat shock protein masks BRCA1 mutations, suggesting a new treatment path

Researchers from The University of Texas MD Anderson Cancer Center identified a new role for heat shock protein 90 (HSP90) in cancer predisposition and treatment resistance.

Their discovery, published in Molecular Cell, demonstrates that HSP90 buffers BRCA1 mutations, masking their negative effects and delaying breast cancer onset. This buffering creates a vulnerability in cancer cells, revealing a potential therapeutic strategy in which targeting HSP90 could be used to overcome treatment resistance.

The study, led by Georgios Karras, Ph.D., associate professor of Genetics, identifies predictive features of HSP90 buffering in patients with specific mutations in BRCA1 that may help personalize diagnosis, prognosis and combination treatments to improve outcomes.

“Mutations are not all the same. Understanding the mechanisms that distinguish them can improve our ability to predict clinical outcomes and to target mutations more effectively in patients,” Karras said.

Heat shock proteins

Heat shock proteins (HSPs) protect cells and tissues from stress caused by misfolded or damaged proteins by helping to repair these damages. HSPs also perform important functions in the absence of stress.

HSP90 helps many proteins fold correctly and acts as a buffer, masking genetic mutations that would otherwise cause protein misfolding and dysfunction. Despite this critical role, the significance of HSP90 buffering for human health has remained unclear, underscoring the need to understand its impact on common genetic diseases.

HSP90 influence BRCA1 mutations and treatment resistance

The BRCA1 gene encodes an essential tumor suppressor that protects against many cancers. Mutations that inactivate BRCA1 can disturb key genome maintenance pathways and predispose individuals to breast and ovarian cancers, in particular.

The researchers discovered that HSP90 buffers against certain mutations in BRCA1, allowing these potentially harmful mutations to persist in populations and delaying the onset of breast cancer in carriers.

Importantly, they found that cancer cells with HSP90-buffered BRCA1 mutations are resistant to PARP inhibitor treatment in a way that depends on HSP90. Although HSP90 can buffer diverse BRCA1 mutations, its ability to do so is easily disrupted by certain environmental changes—such as when a patient has a fever.

Adding a low-dose HSP90 inhibitor overcame resistance to PARP inhibitor treatment in cancer cells carrying HSP90-buffered BRCA1 mutations. Further analysis revealed specific predictive features of HSP90 buffering, enabling better classification of patients most likely to benefit from this combination treatment strategy.

Implications for patients with BRCA1 mutations

Many cancer patients carry HSP90-buffered BRCA1 mutations, suggesting these individuals could benefit from low-dose HSP90 inhibition to enhance their response to PARP inhibitor treatment.

Moreover, potent and highly selective HSP90 inhibitors are already available and beginning to show promise in clinical trials. Still, further clinical research is needed to determine if this is an effective treatment strategy for patients.