MDM2/MDMX inhibition by Sulanemadlin synergizes with anti-Programmed Death 1 immunotherapy in wild-type p53 tumors.

Autor:	Ingelshed K; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden., Melssen MM; Department of Immunology, Genetics and Pathology, Uppsala University, 75185 Uppsala, Sweden., Kannan P; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden., Chandramohan A; MSD International Singapore, Singapore 138665, Singapore., Partridge AW; MSD International Singapore, Singapore 138665, Singapore., Jiang L; Division of Rheumatology, Department of Medicine Solna, Karolinska University Hospital and Karolinska Institutet, 17177 Stockholm, Sweden.; Center for Molecular Medicine, 17176 Stockholm, Sweden., Wermeling F; Division of Rheumatology, Department of Medicine Solna, Karolinska University Hospital and Karolinska Institutet, 17177 Stockholm, Sweden.; Center for Molecular Medicine, 17176 Stockholm, Sweden., Lane DP; Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden., Nestor M; Department of Immunology, Genetics and Pathology, Uppsala University, 75185 Uppsala, Sweden., Spiegelberg D; Department of Immunology, Genetics and Pathology, Uppsala University, 75185 Uppsala, Sweden.; Department of Surgical Sciences, Uppsala University, 75185 Uppsala, Sweden.
Jazyk:	angličtina
Zdroj:	IScience [iScience] 2024 May 06; Vol. 27 (6), pp. 109862. Date of Electronic Publication: 2024 May 06 (Print Publication: 2024).
DOI:	10.1016/j.isci.2024.109862
Abstrakt:	Immunotherapy has revolutionized cancer treatment but its efficacy depends on a robust immune response in the tumor. Silencing of the tumor suppressor p53 is common in tumors and can affect the recruitment and activation of different immune cells, leading to immune evasion and poor therapy response. We found that the p53 activating stapled peptide MDM2/MDMX inhibitor Sulanemadlin (ALRN-6924) inhibited p53 wild-type cancer cell growth in vitro and in vivo . In mice carrying p53 wild-type CT26.WT tumors, monotherapy with the PD-1 inhibitor DX400 or Sulanemadlin delayed tumor doubling time by 50% and 37%, respectively, while combination therapy decreased tumor doubling time by 93% leading to an increased median survival time. Sulanemadlin treatment led to increased immunogenicity and combination treatment with PD-1 inhibition resulted in an increased tumor infiltration of lymphocytes. This combination treatment strategy could potentially turn partial responders into responders of immunotherapy, expanding the patient target group for PD-1-targeting immunotherapy. Competing Interests: AWP was formerly an employee of MSD and is currently an employee of Genentech, companies that are active in the fields of oncology and immuno-oncology. DPL is the Chairman of Chugai Pharmabody PTE LTD and a founder of FOG Pharma. This work and other work in the laboratory of DPL were supported by Merck Pharmaceuticals. (© 2024 The Author(s).)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu