Session 3:  Cancer therapeutic innovations

From PARP to targeting MTHFD1/2 for cancer specific folate trapping

Damage at DNA replication forks are central to both cancer development and treatment. Here, I describe how different DNA repair pathways collaborate at replication forks and how this is key for cancer cell survival and suppressing mutations and cancer development. This work led up to the identification of the synthetic lethal concept; treating BRCA1 or BRCA2 mutated homologous recombination defective cancers with PARP inhibitors. I describe the early pre-clinical and clinical challenges in developing this concept into the clinic. Further to this I describe the underlying basic science underpinning DNA repair at replication forks and describe a novel highly cancer specific attack on MTHFD1 and MTHFD2. Here we demonstrate a new role for MTHFD2 in DNA replication and genomic stability in cancer cells, and perform a drug screen to identify potent and selective nanomolar dual MTHFD1 and MTHFD2 inhibitors (MTHFD1/2i). We show protein co-crystal structures demonstrated binding to the active site of MTHFD1/2 and target engagement. MTHFD1/2i reduced replication fork speed and induced replication stress followed by S phase arrest and apoptosis of cancer cells in vitro and in vivo, with a therapeutic window spanning four orders of magnitude compared to non-transformed cells. Mechanistically, MTHFD1/2i prevented thymidine production leading to mis-incorporation of uracil into DNA and replication stress. Overall, these results demonstrate a functional link between MTHFD2-dependent cancer metabolism and replication stress that can be exploited therapeutically with this new class of inhibitors.