Synergistic antitumor activity of GLIX1, a small molecule TET2 activator, in combination with PARP inhibition across multiple cancers.

Abstract

e13129 Background: Poly(ADP-ribose) polymerase (PARP) detects single-stranded DNA breaks and marks them for repair. PARP inhibitors (PARPi) interfere with PARP activity, stabilizing single-stranded DNA breaks, inducing synthetic lethality in tumors with defects in homologous recombination repair. These inhibitors have limited activity in most homologous recombination (HR)–proficient cancers. Expansion of PARPi utility into HR-proficient cancers requires strategies that increase tumor-selective DNA damage and dependence on PARP-mediated repair. Ten-Eleven Translocation methylcytosine dioxygenase 2 (TET2) catalyzes the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxycytosine -- the latter two species are substrates for base excision repair generating a single-stranded DNA break. Cancers have an increase in hypermethylated regions and TET2 is inhibited. GLIX1 is a small-molecule activator of TET2 that is designed to promote tumor-selective DNA single-strand breaks through increased DNA oxidation and base excision repair. Mechanistically, GLIX1 is expected to increase the formation of tumor-selective single-stranded DNA breaks, while PARP inhibition is expected to stabilize these lesions, resulting in enhanced cancer cell death. Methods: In vitro combination studies were performed across a panel of cancer cell lines representing multiple tumor types. GLIX1 was evaluated in combination with a range of clinically relevant PARPi using dose–response matrices and quantitative synergy modeling. Results: The combination of GLIX1 with PARPi produced strong and reproducible synergistic cytotoxicity across a range of cancer cell lines and tumor subtypes, including those not typically sensitive to PARP inhibition. Synergy was observed across multiple PARPi with differing chemical scaffolds and trapping potency, supporting a class effect rather than compound-specific activity. Conclusions: These data demonstrate broad in vitro synergy between GLIX1 and PARP inhibition across diverse cancers. The complementary mechanisms of GLIX1-mediated DNA modification and PARP-dependent DNA repair provide a strong mechanistic rationale for combination therapy and support further translational and clinical evaluation.