DR-522 Understand mechanism of resistance in HR deficient cancers

Patients with homologous recombination deficiency (HRD), a condition when cancer cells cannot effectively repair DNA double-strand breaks. HRD tumours, especially those with BRCA1/2 mutations, are vulnerable to PARP inhibitors and platinum-based chemotherapies. These drugs block the repair of single-strand DNA breaks, which in HRD cells leads to accumulation of double-strand breaks, and ultimately cause cancer cell death. While initial responses to HRD targeting therapies are strong, resistance mechanisms (e.g., reversion mutations, loss of Shieldin complex) can emerge over time, reducing long-term benefit. Ongoing research is focused on combination therapies and next-generation inhibitors to overcome this, and also on defining biomarkers of resistance.  These biomarkers can derive significant clinical benefit from targeted therapies, particularly PARP inhibitors and platinum-based chemotherapies by identifying patients where the therapy would work and sparing those from side effects where these therapies are not suitable.

Syed Haider, The Institute of Cancer Research, United Kingdom