No abstract

Metabolic reprograming is an emerging hallmark of tumor biology and an actively pursued opportunity in discovery of oncology drugs. Extensive efforts have focused on therapeutic targeting of glycolysis, whereas drugging mitochondrial oxidative phosphorylation (OXPHOS) has remained largely unexplored, partly owing to an incomplete understanding of tumor contexts in which OXPHOS is essential. Here, we report the discovery of IACS-010759, a clinical-grade small-molecule inhibitor of complex I of the mitochondrial electron transport chain. Treatment with IACS-010759 robustly inhibited proliferation and induced apoptosis in models of brain cancer and acute myeloid leukemia (AML) reliant on OXPHOS, likely owing to a combination of energy depletion and reduced aspartate production that leads to impaired nucleotide biosynthesis. In models of brain cancer and AML, tumor growth was potently inhibited in vivo following IACS-010759 treatment at well-tolerated doses. IACS-010759 is currently being evaluated in phase 1 clinical trials in relapsed/refractory AML and solid tumors.

The repair of chromosomal double strand breaks (DSBs) is crucial in the maintenance of genomic integrity. However, the repair of DSBs can also destabilize the genome by causing mutations and chromosomal rearrangements, the driving forces for carcinogenesis and hereditary diseases. Break induced replication (BIR) is one of the DSB repair pathways that is highly prone to genetic instability1–3. BIR proceeds by invasion of one broken end into a homologous DNA sequence followed by replication that can copy hundreds of kilobasepairs of DNA from a donor molecule all the way through its telomere4,5. The resulting repaired chromosome comes at a great cost to the cell, as BIR promotes mutagenesis, loss of heterozygosity, translocations, and copy number variations, all hallmarks of carcinogenesis4–9. BIR employs the majority of known replication proteins to copy large portions of DNA, similar to S-phase replication10,11. It has thus been suggested that BIR proceeds by semiconservative replication; however, the model of a bona-fide, stable replication fork contradicts the known instabilities associated with BIR such as a 1000-fold increase in mutation rate compared to normal replication9. Here we demonstrate that the mechanism of replication during BIR is significantly different from S-phase replication, as it proceeds via an unusual bubble-like replication fork that results in conservative inheritance of the new genetic material. We provide the evidence that this atypical mode of DNA replication, dependent on Pif1 helicase, is responsible for the dramatic increase in BIR-associated mutations. We propose that the BIR-mode of synthesis presents a powerful mechanism that can initiate bursts of genetic instability in eukaryotes including humans.

DNA replication initiated by one-ended homologous recombination at a double-strand break is highly inaccurate, as it greatly stimulates frameshift mutations over the entire path of the replication fork.