Targeting the mevalonate or Wnt pathways to overcome CAR T-cell resistance in TP53-mutant AML cells

• Published in: EMBO molecular medicine 2024-03, Vol.16 (3), p.445-474
• Main Authors: Mueller, Jan, Schimmer, Roman R, Koch, Christian, Schneiter, Florin, Fullin, Jonas, Lysenko, Veronika, Pellegrino, Christian, Klemm, Nancy, Russkamp, Norman, Myburgh, Renier, Volta, Laura, Theocharides, Alexandre PA, Kurppa, Kari J, Ebert, Benjamin L, Schroeder, Timm, Manz, Markus G, Boettcher, Steffen
• Format: Article
• Language: English
• Subjects: AML; Biomedical and Life Sciences; Biomedicine; CAR T-Cell Therapy; EMBO03; EMBO18; EMBO19; Mevalonate Pathway; Molecular Medicine; TP53 Mutations
• ISSN: 1757-4684; 1757-4684
• DOI: 10.1038/s44321-024-00024-2

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. Synopsis TP53 mutations in AML confer resistance to CAR T-cell therapy through exhaustion of CAR T-cells, and dysregulation of the mevalonate and Wnt pathways in AML and CAR T-cells, respectively. Targeting these pathways holds the promise to improve cellular therapies for TP53 -mutant myeloid neoplasms. TP53 deficiency in AML cells leads to CAR T-cell exhaustion and ultimately AML resistance and outgrowth. TP53 -deficient AML cells upregulate the mevalonate pathway upon CAR T-cell attack. CAR T-cells engaging TP53 -deficient AML cells exhibit a downregulated Wnt pathway. Inhibition of the mevalonate pathway in TP53 -deficient AML cells or enhancing the Wnt pathway in CAR T-cells restores efficient CAR T-cell-mediated AML cell lysis. TP53 mutations in AML confer resistance to CAR T-cell therapy through exhaustion of CAR T-cells, and dysregulation of the mevalonate and Wnt pathways in AML and CAR T-cells, respectively. Targeting these pathways holds the promise to improve cellular therapies for TP53 -mutant myeloid neoplasms.