Targeting Polθ Helicase with RP-3467: Preclinical Validation and Clinical Response in a gBRCA1 ovarian cancer patient with an acquired PARPi resistance mutation in TP53BP1

The article describes the development and testing of a novel drug RP-3467, which inhibits DNA polymerase theta (Polθ), a key enzyme in the DNA repair mechanism called MMEJ. This drug was tested on cancer cells with homologous recombination (HR) deficiency, which are susceptible to PARP inhibitors. In preclinical studies, RP-3467 showed strong synergy with existing PARP inhibitors (olaparib and rucaparib) and achieved sustained tumor regression without additional toxicity. In a phase 1 clinical trial (NCT06560632), a patient with ovarian cancer and a BRCA1 mutation achieved a partial response to the combination of RP-3467 and olaparib. Genetic analysis revealed a mutation in the TP53BP1 gene, previously associated with PARP inhibitor resistance. The results suggest that Polθ inhibition could overcome PARP inhibitor resistance and offer a new therapeutic approach for cancers with HR deficiency.