18P - PARP1 trapping and hyperactivation by the decoy agonist OX425 induces DNA repair abrogation and a robust anti-tumor immune response

Background

Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) lead to synthetic lethality when used in cancers with homologous recombination deficiency (HRD). Despite clinical benefits of PARPi, this treatment is associated with the development of resistance of HRD tumors. Here, we describe the anticancer effects of OX425, a first-in-class oligodeoxynucleotide that operates as a PARP1 decoy, resulting in constitutive PARP1 hyperactivation and consequent exhaustion of the DNA damage response.

Methods

OX425-induced PARP trapping, hyperactivation and cell cytotoxicity were examined in vitro in HRD and homologous recombination proficient (HRP) human cancer cells, as well as in non-transformed cell lines. DNA repair efficacy was monitored by analyzing repair protein recruitment to damage sites. RNAseq analysis in HRP/HRD tumor cells treated with OX425 or PARP inhibitors was employed to uncover the molecular mechanisms underlying OX425 effects. The anticancer efficacy of OX425 was assessed in vivo in different HRD and HRP tumor models, including endogenous mammary carcinomas as driven in immunocompetent female mice by MPA plus DMBA.

Results

At odds with conventional PARP inhibitors, OX425 bound to and hyperactivated PARP1 with high affinity in a dose-dependent manner, resulting in elevated cytotoxicity to multiple cancer cells with slight benefits to HRD cancers. Moreover, long-term treatment with OX425 did not show any mutagenicity compared to PARPi. The activity of OX425 was specific to tumor cells, as no significant effect on cell viability was observed for normal cells, at odds with PARP inhibitors. In line with in vitro results, OX425 mediated considerable anticancer effects in vivo as it generated an immunologically active tumor microenvironment. Importantly, OX425 treatment significantly delayed acquired resistance to olaparib in BRCA1 mutated MDA-MB-436 cell-derived xenografts.

Conclusions

Our results provide a safety profile and preclinical rationale for using OX425 in patients bearing HRD tumors, to trigger DNA damage exhaustion and initiate inflammatory responses in the tumor microenvironment.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Onxeo.

Disclosure

V. Zakharova, C. Doizelet, V. Hayes, W. Jdey: Financial Interests, Institutional, Full or part-time Employment: onxeo. All other authors have declared no conflicts of interest.