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

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

  • EMBO Mol Med. 2024 Feb 14. doi: 10.1038/s44321-024-00024-2.
Jan Mueller # 1 Roman R Schimmer # 1 Christian Koch 1 Florin Schneiter 2 Jonas Fullin 1 Veronika Lysenko 1 Christian Pellegrino 1 Nancy Klemm 1 Norman Russkamp 1 Renier Myburgh 1 Laura Volta 1 Alexandre Pa Theocharides 1 Kari J Kurppa 3 Benjamin L Ebert 4 Timm Schroeder 2 Markus G Manz # 1 Steffen Boettcher # 5
Affiliations

Affiliations

  • 1 Department of Medical Oncology and Hematology, University of Zurich and University Hospital Zurich, Zurich, Switzerland.
  • 2 Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland.
  • 3 Institute of Biomedicine and Medicity Research Laboratories, University of Turku, Turku, Finland.
  • 4 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 5 Department of Medical Oncology and Hematology, University of Zurich and University Hospital Zurich, Zurich, Switzerland. steffen.boettcher@usz.ch.
  • # Contributed equally.
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.

Keywords

AML; CAR T-Cell Therapy; Mevalonate Pathway; TP53 Mutations.

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