The Dutch Cancer Society (KWF Kankerbestrijding) has awarded a total of 5.5 million euro to ten Amsterdam UMC research groups for cancer research. One of the project proposals selected is entitled “Exploiting PARP Inhibition as a Strategy to Treat STAG2 Deficient Tumors” by principal investigator Dr. Job de Lange, and co-applicants Prof. Connie Jimenez and Dr. Rob Wolthuis (€ 464.028). Their teams will investigate how mutations in a tumor suppressor gene (STAG2) increase the sensitivity to anti-cancer therapy (PARP inhibitors).
PARP inhibition (PARPi) has shown clinical benefit in breast and ovarian cancers with defective homologous recombination. Work from us and others suggests that also inactivation of the tumor suppressor STAG2 sensitizes to PARPi, which would significantly expand its clinical exploitation. STAG2 directly binds the protein complex cohesin, which has multiple roles in genome organization. Despite its high mutation rate in cancer, relatively little research has been done on STAG2. Importantly, recent findings indicate that STAG2 affects the dynamic loading and unloading of cohesin (‘cohesin dynamics’) at DNA replication forks. Furthermore, the toxicity of PARPi is mainly due to its effect at DNA replication forks. Thus, the PARPi response of STAG2 deficient cells may be affected by deregulated cohesin dynamics at stalled DNA replication forks.
We aim to identify what factors determine the PARPi sensitivity of STAG2 deficient cells. We will perform unbiased genetic and proteomic screens In STAG2 depleted and PARPi treated cells, as well as multiple dedicated assessments of relevant cellular processes. These efforts aim to both provide important fundamental insights, and identify biomarkers and targets for optimized therapy responses.
