DNA-Dependent Protein Kinase Inhibitor Peposertib Enhances Efficacy of177Lu-Based Radioimmunotherapy in Preclinical Models of Prostate and Renal Cell Carcinoma

Novel radiation sensitizers, including inhibitors targeting DNA damage response, have been developed to enhance the efficacy of anticancer treatments that induce DNA damage in cancer cells. Peposertib, a potent, selective, and orally administered inhibitor of DNA-dependent protein kinase, impedes the nonhomologous end-joining mechanism for DNA double-strand break (DSB) repair. We investigated radioimmunotherapy alone or with peposertib in preclinical models of renal cell carcinoma (RCC) or prostate cancer. Methods: ¹⁷⁷Lu-DOTA-girentuximab (targeting carbonic anhydrase IX) or ¹⁷⁷Lu-DOTA-rosopatamab (targeting prostate-specific membrane antigen) was used to deliver β-radiation to tumors via a single intravenous dose (3 or 6 MBq) in mice bearing SK-RC-52 RCC or LNCaP prostate cancer xenografts, respectively. Peposertib (50 mg/kg daily for 14 d) was administered via oral gavage. Biodistribution and in vivo imaging of ¹⁷⁷Lu-based radioimmunotherapy were performed for both preclinical models. Tumor growth and body weight were monitored until the endpoint. Assessment of DNA damage was performed by measuring DSBs through analysis of γH2AX foci formation in tumor sections. Results: Ex vivo biodistribution and in vivo SPECT/MRI revealed excellent tumor uptake of each radiopharmaceutical. Mouse body weight was stable in all treatment arms. Peposertib alone did not show a significant antitumor effect. The addition of peposertib to ¹⁷⁷Lu-DOTA-girentuximab showed enhanced antitumor efficacy compared with ¹⁷⁷Lu-DOTA-girentuximab alone in the SK-RC-52 animal model, with a 4 of 4 complete response rate in the ¹⁷⁷Lu-DOTA-girentuximab (6 MBq) plus peposertib arm. Peposertib combined with low-dose ¹⁷⁷Lu-DOTA-girentuximab (3 MBq) demonstrated antitumor activity comparable to ¹⁷⁷Lu-DOTA-girentuximab (6 MBq) monotherapy. In the LNCaP prostate cancer model, the combination of ¹⁷⁷Lu-DOTA-rosopatamab (6 MBq) and peposertib achieved a 3 of 4 complete response rate. Increased DSBs were observed with the addition of peposertib to ¹⁷⁷Lu-based radioimmunotherapy. Conclusion: The combination of peposertib with ¹⁷⁷Lu-based radioimmunotherapy was well tolerated in preclinical models of RCC and prostate cancer. Our findings suggest a synergistic effect between peposertib and ¹⁷⁷Lu-based radioimmunotherapy, wherein peposertib enhanced the efficacy of radioimmunotherapy. This synergy indicates the potential to reduce the necessary dose of radioimmunotherapy for effective cancer treatment.