A study published in *Nature* (2008) reveals that secondary mutations in the BRCA2 gene can lead to cisplatin resistance in BRCA2-mutated cancers. BRCA2 is a tumor suppressor gene critical for DNA repair, and mutations in it are associated with increased cancer risk. In BRCA2-mutated cancers, such as ovarian and breast cancers, cisplatin is initially effective, but resistance often develops. The study shows that resistance can be caused by secondary mutations that restore the BRCA2 reading frame, allowing the protein to function again. In experiments, researchers found that in a cisplatin-resistant breast cancer cell line (HCC1428), a secondary mutation in BRCA2 restored its function. Similarly, in a pancreatic cancer cell line (Capan-1), cisplatin selection led to five secondary mutations that restored the BRCA2 reading frame. These mutations allowed the cancer cells to resist both cisplatin and PARP inhibitors. In patients with BRCA2-mutated ovarian cancer, recurrent tumors that had developed cisplatin resistance showed reversion of their BRCA2 mutation, suggesting that secondary mutations are a key mechanism of resistance. The study also found that BRCA2-deficient cancer cells are highly sensitive to cisplatin, but secondary mutations can restore BRCA2 function, leading to resistance. These mutations can occur in response to chemotherapy, and their presence may indicate that tumors are likely to be resistant to both cisplatin and PARP inhibitors. The findings suggest that testing for these secondary mutations in BRCA2-mutated cancers could be clinically important for predicting resistance and guiding treatment. The study highlights the role of BRCA2 in DNA repair and how its mutations can lead to cancer. Secondary mutations that restore BRCA2 function may be a major mechanism of acquired resistance to platinum-based chemotherapy. The research also suggests that drugs like proteasome inhibitors, which block RAD51 recruitment to DNA repair sites, might help re-sensitize resistant tumors to cisplatin and PARP inhibitors. However, tumors without secondary mutations may remain sensitive to PARP inhibitors. The study has implications beyond ovarian cancer, as secondary mutations in BRCA2 have been observed in other cancers, including acute myeloid leukemia and Chinese hamster fibroblasts. These findings contribute to understanding the mechanisms of resistance in BRCA2-mutated cancers and may inform the development of new therapeutic strategies.A study published in *Nature* (2008) reveals that secondary mutations in the BRCA2 gene can lead to cisplatin resistance in BRCA2-mutated cancers. BRCA2 is a tumor suppressor gene critical for DNA repair, and mutations in it are associated with increased cancer risk. In BRCA2-mutated cancers, such as ovarian and breast cancers, cisplatin is initially effective, but resistance often develops. The study shows that resistance can be caused by secondary mutations that restore the BRCA2 reading frame, allowing the protein to function again. In experiments, researchers found that in a cisplatin-resistant breast cancer cell line (HCC1428), a secondary mutation in BRCA2 restored its function. Similarly, in a pancreatic cancer cell line (Capan-1), cisplatin selection led to five secondary mutations that restored the BRCA2 reading frame. These mutations allowed the cancer cells to resist both cisplatin and PARP inhibitors. In patients with BRCA2-mutated ovarian cancer, recurrent tumors that had developed cisplatin resistance showed reversion of their BRCA2 mutation, suggesting that secondary mutations are a key mechanism of resistance. The study also found that BRCA2-deficient cancer cells are highly sensitive to cisplatin, but secondary mutations can restore BRCA2 function, leading to resistance. These mutations can occur in response to chemotherapy, and their presence may indicate that tumors are likely to be resistant to both cisplatin and PARP inhibitors. The findings suggest that testing for these secondary mutations in BRCA2-mutated cancers could be clinically important for predicting resistance and guiding treatment. The study highlights the role of BRCA2 in DNA repair and how its mutations can lead to cancer. Secondary mutations that restore BRCA2 function may be a major mechanism of acquired resistance to platinum-based chemotherapy. The research also suggests that drugs like proteasome inhibitors, which block RAD51 recruitment to DNA repair sites, might help re-sensitize resistant tumors to cisplatin and PARP inhibitors. However, tumors without secondary mutations may remain sensitive to PARP inhibitors. The study has implications beyond ovarian cancer, as secondary mutations in BRCA2 have been observed in other cancers, including acute myeloid leukemia and Chinese hamster fibroblasts. These findings contribute to understanding the mechanisms of resistance in BRCA2-mutated cancers and may inform the development of new therapeutic strategies.