Inhibition of Poly(ADP-ribose) Polymerase Sensitizes [177Lu]Lu-DOTAGA.(SA.FAPi)2-Mediated Radiotherapy in Triple-Negative Breast Cancer

Fibroblast activation protein (FAP) is highly expressed in many tumor types and constitutes a promising target for tumor-specific delivery of therapeutic radionuclides. [177Lu]Lu-DOTAGA.(SA.FAPi)2 is a novel radiopharmaceutical based on a novel bidentate inhibitor of FAP that is excreted more slowly than its monomeric counterparts. Still, the efficacy of radiotherapy is mitigated by cascades of DNA damage repair signaling in tumor cells including those via Poly(ADP-ribose) polymerase (PARP). We hereby aimed to evaluate the efficacy of [177Lu]Lu-DOTAGA.(SA.FAPi)2 in combination with a PARP inhibitor, Olaparib, in the 4T1 murine triple negative breast cancer (TNBC) model. The therapeutic efficacy was visualized using 18F-FDG and [68Ga]Ga-FAPI-04 positron emission imaging/computer tomography (PET/CT). Our results demonstrated that Olaparib suppressed BALB/3T3 fibroblasts in vitro and sensitized the efficacy of [177Lu]Lu-DOTAGA.(SA.FAPi)2 in mice bearing 4T1 tumors via enhancement of DNA damage. Treatment-associated toxicity was tolerable with only mild leukopenia. Therefore, the combination of [177Lu]Lu-DOTAGA.(SA.FAPi)2 and Olaparib is a feasible treatment against TNBC.