Breast and ovarian cancers with faulty BRCA1 or BRCA2 genes often accumulate single-stranded DNA gaps during replication, and researchers now have the tools to test whether these gaps are a hidden vulnerability that existing treatments fail to exploit. The problem is that current therapies—PARP inhibitors and platinum drugs—stop working in roughly half of patients who initially respond, and many tumours never respond at all. Scientists know these drugs rely on the inability of BRCA-deficient cells to repair double-strand breaks, but they disagree about whether the accumulation of single-stranded DNA gaps also drives sensitivity. Without knowing which defect matters most, it is impossible to design better treatments or identify which patients will benefit. This project uses specially engineered cells that separate the two defects—cells that can repair double-strand breaks but still accumulate gaps. If the team proves that gaps directly cause drug sensitivity, it could redefine how clinicians classify and treat BRCA-mutant cancers. The findings might lead to a new category of “gap-prone” tumours, improve patient stratification, and guide the development of therapies for resistant cancers. Even if the work remains fundamental, it will clarify a long-standing controversy in DNA repair biology and provide a mechanistic foundation for future drug design.
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BRCA1 and BRCA2-mutant cancers are often treated with poly(ADP-ribose) polymerase inhibitors (PARPi) and platinum-based therapies. BRCA1 and BRCA2-deficient cells are well known to lack homologous recombination repair of DNA double-strand breaks, and this lack is critical to responses to current therapies. They also suffer from replication-associated defects, particularly the accumulation of single-stranded DNA (ssDNA) gaps made by error-prone DNA replication. The degree to which such gaps contribute to therapy sensitivity is controversial, with some evidence suggesting they may be a central driver of emerging therapies and contribute to PARPi sensitivity, if not sufficient in themselves. Many BRCA1 and BRCA2 mutant cancers do not respond to current therapies and nearly half of initial responders develop resistance. To overcome this, new therapeutic approaches are currently being investigated in early-phase clinical trials that exploit BRCA1/2 loss or enhance sensitivity to existing treatments. Emerging evidence from studies of some of these new therapeutic approaches points to a role in ssDNA gap generation or expansion in BRCA1 and BRCA2 mutant cancer cells. The degree to which the presence of ssDNA gaps in mutant cells directly contributes to various therapy sensitivities is a critical question with implications for patient stratification and the design and use of therapies currently thought to target homologous recombination defects. For example, while the restoration of homologous recombination represents a known mechanism of therapy resistance, the extent to which gap-related vulnerabilities persist remains uncertain. Likewise, it is currently unclear whether "gap-prone" cancers might constitute a distinct and therapeutically targetable category, analogous to but separate from homologous recombination repair–deficient cancers. The multiple defects of cells lacking BRCA1 and BRCA2 make it challenging to isolate the contributions of particular roles. Understanding these roles alone, and in concert with each other, is important to avoid oversimplified models that limit therapeutic innovation. Fortunately, recent discoveries have shown that some replication functions depend on particular activities of these proteins, making it possible to identify separation-of-function variants that retain homologous recombination DNA repair but lose certain replication functions. We have made and tested cells with these specific changes and can now independently assess the relative contribution of some replication difficulties, including, importantly, the accumulation of ssDNA gaps. Our preliminary data indicates that ssDNA gaps are indeed relevant to several therapy responses. They also suggest that the way BRCA1 and BRCA2 prevent the gaps differs. We aim to uncover how ssDNA gaps are formed, the relationship between BRCA1 and BRCA2 in this pathway, determine how ssDNA gaps might be targeted to enhance therapeutic vulnerabilities, and test whether they predict responses in resistant models. The results of the project will provide critical mechanistic insight into therapy sensitivity. They may also provide the basis, in the form of ssDNA gaps or related features, to improve patient stratification and help design rational therapies for refractory and resistant BRCA1/2-mutant cancers. These findings will benefit researchers with an interest in DNA replication and repair, pharmaceutical companies, clinicians, and ultimately patients and their families.
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