Abstract 590: Prostate specific membrane antigen targeted PRMT5 inhibition re-sensitizes cancer cells to radiation therapies

Abstract Prostate cancer (PCa) is the second most common cause of cancer-related deaths in US men. Although treatment with the targeted radioligand therapy, 177Lu-PSMA-617 (Pluvicto®) has significantly improved outcomes of patients who progress on androgen deprivation therapy, development of resistance to Pluvicto via upregulation of DNA damage repair enzymes has remained a major impediment to achievement of complete responses. To prevent emergence of this resistance, DNA damage repair inhibitors (DDRIs) have been explored with some success, however, their efficacies are limited by significant off-target toxicities. To avoid these toxicities, we have designed prostate specific membrane antigen (PSMA)-targeted DDRIs comprised of the same targeting ligand used in Pluvicto, but linked to a DDRI instead of a radionuclide. In the studies summarized here, we conjugate an inhibitor of protein arginine methyltransferase 5 (PRMT5), i.e. a master regulator of DNA damage repair that is overexpressed in response to ionizing radiation, to the small ligand PSMA-617, and examine its impact on the treatment of PCa tumor bearing mice with 177 Lu-Pluvicto. Briefly, a releasable PSMA-targeted PRMT5 inhibitor (PSMA-PRMT5i) was synthesized and tested for its binding affinity and efficacy in PSMA-expressing LNCaP cells. PSMA-PRMT5i was found to bind PSMA on LNCaP cells in culture with high affinity (Kd = 1.5 nM) and significantly reduce their survival following exposure to 2Gy of beam radiation. Quantitative analysis of the radiation-induced DNA double-strand breaks showed that PSMA-PRMT5i increased the number of DNA double-strand breaks by a factor of two, even at the very low concentration of 1 nM, whereas non-targeted PRMT5 inhibitor had no impact at the same concentration. Finally, analysis of antitumor activity in LNCaP tumor bearing mice demonstrated that the targeted PSMA-PRMT5i reduced tumor growth by 90% when used in combination with 177 Lu-Pluvicto, whereas 177 Lu-Pluvicto alone suppressed tumor growth by only 50%. Not surprisingly, co-administration of PSMA-PRMT5i similarly increased the efficacy of beam radiation from 50% to 90% tumor suppression at the same concentration (10 nmol/mouse/day). Because no therapeutic benefit could be detected in mice treated with the same concentration of nontargeted PRMT5i, and since no loss in animal body weight was observed in any of the treatment groups, we conclude that low dose PSMA-PRMT5i can significantly improve radiation therapies outcomes with little or no accompanying toxicity. Citation Format: Sagnik Sengupta, Sudarsan Reddy Kasireddy, Ramesh Mukkamala, Madduri Srinivasarao, Philip S. Low. Prostate specific membrane antigen targeted PRMT5 inhibition re-sensitizes cancer cells to radiation therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 590.