Abstract 4231: Preclinical candidate RVU305, an MTA-cooperative PRMT5 inhibitor, shows activity in MTAP-deleted tumors resistant to immune checkpoint treatment

Abstract Homozygous deletions of methylthioadenosine phosphorylase (MTAP), located on chromosome 9p21 are observed in 10 to 15% of all human tumors. This deletion leads to a substantial methylthioadenosine (MTA) build-up within cells. At high concentrations, MTA acts as a highly selective inhibitor of the PRMT5 methyltransferase, specifically competing with its substrate, S-adenosylmethionine (SAM). Hence, selectively targeting of residual PRMT5 levels, which are essential for survival of cancers, represents a promising strategy for eliminating cancer cells with homozygous MTAP deletion. There is growing evidence that MTA accumulation enhances immunosuppressive tumor microenvironment. Moreover, tumor-specific PRMT5 inhibition has been shown to enhance antitumor immune responses, opening the possibility of combining MTAP-deletion specific MTA-cooperative PRMT5 inhibitors with cancer immunotherapy. Ryvu has developed RVU305, a potentially best-in-class MTA-cooperative PRMT5 inhibitor, characterized by favorable drug-like physicochemical properties, low nanomolar potency, and differential efficacy in MTAP-null cancer cells. To evaluate the immunomodulatory activity of RVU305, we developed an MC38 syngeneic colon cancer model with homozygous deletion of MTAP and CDKN2A genes. The tumor growth inhibitory activity of RVU305 was assessed following oral administration, both alone and in combination with anti-PD-1 antibody. Effects on tumor-infiltrating lymphocytes were analyzed using flow cytometry. Changes in IFN-γ-secreting T cells were evaluated using ELISpot. PRMT5 inhibition in MTAP-null cancer cells, as well as in stromal and infiltrating lymphocytes, was assessed via SDMA IHC staining. RVU305 demonstrated robust tumor growth inhibition (TGI) in MC38 tumors with MTAP loss, with confirmed target engagement, while the growth of the MC38 variant with an intact MTAP gene was unaffected at pharmacologically active doses. Furthermore, co-treatment with RVU305 and anti-PD-1 antibody was well tolerated and resulted in antitumor activity. Immunomodulatory effects of RVU305, both alone and in combination with anti-PD-1, were supported by pharmacodynamic changes observed in tumor tissue. Taken together, these studies confirm that MTA-cooperative PRMT5 inhibitors induce a strong synthetic lethal phenotype in MTAP-deleted cancers, offering an exciting therapeutic opportunity for a large patient population and potentially addressing an unmet clinical need when combined with immunotherapy. Citation Format: Anna Bartosik, Adam Radzimierski, Aneta Bobowska, Aleksandra Więckowska, Kamil Kuś, Jacek Faber, Bożena Winnik, Agata Stachowicz-Wałaszek, Agnieszka Ludwig-Słomczyńska, Kamila Kozłowska-Tomczyk, Marta Wadowska, Szymon Woroszyło, Mateusz Stoszko, Aniela Gołas, Paulina Podkalicka, Adrian Zarębski, Agnieszka Piątek, Maciej Kujawa, Beata Kowalska, Julia Wirkijowska, Stefan Chmielewski, Jacek Stępniewski, Mateusz Ogórek, Lika Osugui, Agnieszka Szymula, Agnieszka Dorman, Kamila Białkowska, Marcelina Chmiel, Milena Mazan, Tomasz Rzymski, Karolina Gluza, Joanna Krawczyk, Marcin Kowiel, Adam Marciniak, Michał Combik, Oleksii Bryzghalov, Mateusz Nowak, Didier Pez, Krzysztof Brzózka. Preclinical candidate RVU305, an MTA-cooperative PRMT5 inhibitor, shows activity in MTAP-deleted tumors resistant to immune checkpoint treatment [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 4231.