{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Mueller J"],"funding":["Jacques and Gloria Gossweiler Foundation","Promedica Foundation Chur","Dr. Walter & Edit Fischli","Fondation Peter Anton & Anna Katharina Miescher pour la Recherche en Hématologie","Clinical Research Prioriy Program “ImmunoCure” of the University of Zurich","Swiss Society of Hematology","KRAK - Physician Scientist Fellowship","Swiss Cancer League","University Research Priority Project Translational Cancer Research Grant"],"pagination":["445-474"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10940689"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["16(3)"],"pubmed_abstract":["TP53-mutant acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS) are characterized by chemotherapy resistance and represent an unmet clinical need. Chimeric antigen receptor (CAR) T-cells might be a promising therapeutic option for TP53-mutant AML/MDS. However, the impact of TP53 deficiency in AML cells on the efficacy of CAR T-cells is unknown. We here show that CAR T-cells engaging TP53-deficient leukemia cells exhibit a prolonged interaction time, upregulate exhaustion markers, and are inefficient to control AML cell outgrowth in vitro and in vivo compared to TP53 wild-type cells. Transcriptional profiling revealed that the mevalonate pathway is upregulated in TP53-deficient AML cells under CAR T-cell attack, while CAR T-cells engaging TP53-deficient AML cells downregulate the Wnt pathway. In vitro rational targeting of either of these pathways rescues AML cell sensitivity to CAR T-cell-mediated killing. We thus demonstrate that TP53 deficiency confers resistance to CAR T-cell therapy and identify the mevalonate pathway as a therapeutic vulnerability of TP53-deficient AML cells engaged by CAR T-cells, and the Wnt pathway as a promising CAR T-cell therapy-enhancing approach for TP53-deficient AML/MDS."],"journal":["EMBO molecular medicine"],"pubmed_title":["Targeting the mevalonate or Wnt pathways to overcome CAR T-cell resistance in TP53-mutant AML cells."],"pmcid":["PMC10940689"],"funding_grant_id":["KFS-4885-08-2019"],"pubmed_authors":["Schimmer RR","Schneiter F","Myburgh R","Fullin J","Volta L","Pellegrino C","Ebert BL","Schroeder T","Koch C","Russkamp N","Lysenko V","Theocharides AP","Manz MG","Klemm N","Kurppa KJ","Mueller J","Boettcher S"],"additional_accession":[]},"is_claimable":false,"name":"Targeting the mevalonate or Wnt pathways to overcome CAR T-cell resistance in TP53-mutant AML cells.","description":"TP53-mutant acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS) are characterized by chemotherapy resistance and represent an unmet clinical need. Chimeric antigen receptor (CAR) T-cells might be a promising therapeutic option for TP53-mutant AML/MDS. However, the impact of TP53 deficiency in AML cells on the efficacy of CAR T-cells is unknown. We here show that CAR T-cells engaging TP53-deficient leukemia cells exhibit a prolonged interaction time, upregulate exhaustion markers, and are inefficient to control AML cell outgrowth in vitro and in vivo compared to TP53 wild-type cells. Transcriptional profiling revealed that the mevalonate pathway is upregulated in TP53-deficient AML cells under CAR T-cell attack, while CAR T-cells engaging TP53-deficient AML cells downregulate the Wnt pathway. In vitro rational targeting of either of these pathways rescues AML cell sensitivity to CAR T-cell-mediated killing. We thus demonstrate that TP53 deficiency confers resistance to CAR T-cell therapy and identify the mevalonate pathway as a therapeutic vulnerability of TP53-deficient AML cells engaged by CAR T-cells, and the Wnt pathway as a promising CAR T-cell therapy-enhancing approach for TP53-deficient AML/MDS.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Mar","modification":"2025-04-05T12:05:59.328Z","creation":"2025-04-05T12:05:59.328Z"},"accession":"S-EPMC10940689","cross_references":{"pubmed":["38355749"],"doi":["10.1038/s44321-024-00024-2"]}}