New Insights Into BRCA2 Deficiency Uncover How Tumors Resist Chemotherapy

Recent scientific advancements have revealed a previously unknown mechanism that enables BRCA2-deficient tumors to develop resistance to chemotherapy, providing crucial insight into overcoming one of oncology's most persistent treatment challenges.

BRCA2 is a key protein involved in the repair of double-stranded DNA breaks through a process known as homologous recombination (HR). Individuals carrying mutations in the BRCA2 gene are at significantly increased risk for breast, ovarian, and prostate cancers due to impaired DNA repair mechanisms. Standard treatment for BRCA2-mutated tumors often involves targeted chemotherapies such as PARP inhibitors, which block an alternative DNA repair pathway. By inhibiting this backup method, cancer cells that cannot perform HR are typically unable to survive, making these drugs highly effective--at least initially.

However, a major limitation of these therapies is the development of chemoresistance over time. Tumors that once responded to treatment eventually regain the ability to repair DNA damage and continue to grow. The precise process by which this resistance arises in BRCA2-deficient cancers has remained elusive until now.

In a collaborative study involving multiple research institutions, scientists have identified the role of the FIGNL1 protein in this phenomenon. Their findings demonstrate that when both BRCA2 and FIGNL1 are absent in cancer cells, the cells regain the ability to repair damaged DNA, making them resistant to chemotherapy. Under normal conditions, BRCA2 is responsible for facilitating the placement of another protein, RAD51, at sites of DNA breaks, enabling HR and maintenance of genomic stability. Without BRCA2, RAD51 cannot adequately bind to DNA, leaving cells vulnerable to damage and sensitive to chemotherapeutic agents.

The research revealed that FIGNL1 acts as a regulator that removes RAD51 from damaged DNA, thereby suppressing HR in BRCA2-deficient cells. Unexpectedly, when FIGNL1 is also absent, the MMS22L-TONSL protein complex compensates by reloading RAD51 onto DNA, effectively restoring the HR process. This alternative pathway allows cancer cells to repair DNA damage and survive, even in the absence of both BRCA2 and FIGNL1.

These discoveries redefine the current understanding of DNA repair in BRCA2-mutated tumors. Previously, BRCA2 was thought to be the primary factor required for RAD51 loading, but the new data suggest a more intricate interplay involving multiple regulatory proteins. In normal cells, BRCA2 and FIGNL1 work in tandem to finely balance RAD51 activity, ensuring optimal DNA repair. Disruption of both proteins, however, activates a backup mechanism via the MMS22L-TONSL complex, which can undermine the effectiveness of targeted chemotherapy.

The implications for cancer therapy are significant. The study suggests that targeting the MMS22L-TONSL complex could potentially prevent or reverse chemoresistance in BRCA2-deficient tumors. By inhibiting this compensatory pathway, it may be possible to sensitize resistant tumors to chemotherapy once again, improving outcomes for patients who have exhausted existing treatment options.

This research opens the door for the development of new therapeutic strategies aimed at overcoming drug resistance in cancers with BRCA2 mutations. Future clinical approaches may involve combination therapies that target both the initial and backup repair pathways, thereby reducing the likelihood of tumor recurrence and enhancing long-term treatment efficacy.

Overall, these findings offer a deeper understanding of the molecular mechanisms driving chemoresistance in BRCA2-related cancers and present promising avenues for more effective, durable treatments in the future.