Researchers uncover mechanism by which BRCA2-deficient tumors develop chemoresistance

One of the biggest challenges in cancer treatment is chemoresistance: tumors that initially respond well to chemotherapy become resistant over time. When that happens, treatment options are often limited.

The research team led by Arnab Ray Chaudhuri has now uncovered a mechanism by which BRCA2-deficient tumors develop this resistance. The proteins BRCA2 and FIGNL1 appear to have a different function than previously assumed. "These findings change the paradigm of thought," says Ray Chaudhuri. The team also identified ways to reverse or prevent resistance.

This breakthrough by Ray Chaudhuri's group at the Department of Molecular Genetics, Erasmus MC Cancer Institute led to a publication in Science, with Oncode Institute researcher Raviprasad Kuthethur as first author.

An unexpected discovery

​Ray Chaudhuri and his team found that removing the protein FIGNL1 in cells lacking BRCA2 restores the HR mechanism. "The outcome was entirely unforeseen," explain Ray Chaudhuri and Kuthethur. "It took us quite some time to fully grasp and accept what was occurring. This ultimately evolved into a multidisciplinary and multi-institutional endeavor, featuring significant collaborations with the labs of Prof. Petr Cejka (IRB, Bellinzona, Switzerland, an Institute affiliated with USI), Dr. Shyam Sharan (NIH, USA), and Prof. Krishna Mohan Poluri (IIT Roorkee, India)."

Further investigation revealed what was happening: FIGNL1 actively removes the protein RAD51 from damaged DNA. Without RAD51, HR cannot occur. But when FIGNL1 is disabled, RAD51 remains in place. This allows the cell to carry out HR even without BRCA2.

BRCA2 as a regulator

The findings shed new light into how BRCA2's role fits into the HR process.

For close to 25 years, people believed that BRCA2 was the most essential factor for loading RAD51 onto damaged DNA, but it seems that might not be the entire story."

Arnab Ray Chaudhuri, Department of Molecular Genetics, Erasmus MC Cancer Institute

BRCA2's function turns out to be more nuanced. In healthy cells, BRCA2 and FIGNL1 work together to maintain balance: BRCA2 helps RAD51 bind to DNA, while FIGNL1 removes it. Together, they fine-tune the amount of RAD51 needed to repair DNA damage.

A backup system

Without regulation by BRCA2 and FIGNL1, RAD51 needs help from another protein complex to perform HR: MMS22L-TONSL. The team discovered that this complex acts as a backup system. In the absence of BRCA2 and FIGNL1, it takes over their role and ensures that enough RAD51 is present on the DNA.

This final discovery has major implications for treating BRCA2-mutated tumors. Tumors that become resistant to chemotherapy use the MMS22L-TONSL pathway to survive. "But if we block MMS22L-TONSL, the entire mechanism collapses," Ray Chaudhuri explains. By targeting this protein complex, tumors could become sensitive to chemotherapy again. This opens new doors for targeted therapies for patients with resistant BRCA2 tumors.