biostudies-literatureMueller JJacques and Gloria Gossweiler FoundationPromedica Foundation ChurDr. Walter & Edit FischliFondation Peter Anton & Anna Katharina Miescher pour la Recherche en HématologieClinical Research Prioriy Program “ImmunoCure” of the University of ZurichSwiss Society of HematologyKRAK - Physician Scientist FellowshipSwiss Cancer LeagueUniversity Research Priority Project Translational Cancer Research Grant445-474https://www.ebi.ac.uk/biostudies/studies/S-EPMC10940689biostudies-literatureUnknown16(3)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.EMBO molecular medicineTargeting the mevalonate or Wnt pathways to overcome CAR T-cell resistance in TP53-mutant AML cells.PMC10940689KFS-4885-08-2019Schimmer RRSchneiter FMyburgh RFullin JVolta LPellegrino CEbert BLSchroeder TKoch CRusskamp NLysenko VTheocharides APManz MGKlemm NKurppa KJMueller JBoettcher SfalseTargeting the mevalonate or Wnt pathways to overcome CAR T-cell resistance in TP53-mutant AML cells.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.2024-01-01T00:00:00Z2024 Mar2025-04-05T12:05:59.328Z2025-04-05T12:05:59.328ZS-EPMC109406893835574910.1038/s44321-024-00024-2