Putting the STING back into BH3-mimetic drugs for TP53-mutant blood cancers

  • Cancer Cell. 2024 Apr 23:S1535-6108(24)00128-4. doi: 10.1016/j.ccell.2024.04.004.
Sarah T Diepstraten  1 ,  Yin Yuan  2 ,  John E La Marca  3 ,  Savannah Young  4 ,  Catherine Chang  4 ,  Lauren Whelan  4 ,  Aisling M Ross  5 ,  Karla C Fischer  6 ,  Giovanna Pomilio  4 ,  Rhiannon Morris  6 ,  Angela Georgiou  4 ,  Veronique Litalien  4 ,  Fiona C Brown  7 ,  Andrew W Roberts  2 ,  Andreas Strasser  6 ,  Andrew H Wei  2 ,  Gemma L Kelly  8
Affiliations
  • 1. Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia. Electronic address: [email protected].
  • 2. Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia; Department of Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC 3050, Australia.
  • 3. Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia; Genome Engineering and Cancer Modelling Program, Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3086, Australia.
  • 4. Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • 5. Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; School of Medicine, Bernal Institute, Limerick Digital Cancer Research Centre & Health Research Institute, University of Limerick, Limerick, Ireland.
  • 6. Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia.
  • 7. Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia; Australian Centre for Blood Diseases, Monash University, Melbourne, VIC 3004, Australia.
  • 8. Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, University of Melbourne, Parkville, VIC 3052, Australia. Electronic address: [email protected].
PMID: 38670091 DOI: 10.1016/j.ccell.2024.04.004
Abstract

TP53-mutant blood cancers remain a clinical challenge. BH3-mimetic drugs inhibit Bcl-2 pro-survival proteins, inducing Cancer cell Apoptosis. Despite acting downstream of p53, functional p53 is required for maximal Cancer cell killing by BH3-mimetics through an unknown mechanism. Here, we report p53 is activated following BH3-mimetic induced mitochondrial outer membrane permeabilization, leading to BH3-only protein induction and thereby potentiating the pro-apoptotic signal. TP53-deficient lymphomas lack this feedforward loop, providing opportunities for survival and disease relapse after BH3-mimetic treatment. The therapeutic barrier imposed by defects in TP53 can be overcome by direct activation of the cGAS/STING pathway, which promotes Apoptosis of blood Cancer cells through p53-independent BH3-only protein upregulation. Combining clinically relevant STING agonists with BH3-mimetic drugs efficiently kills TRP53/TP53-mutant mouse B lymphoma, human NK/T lymphoma, and acute myeloid leukemia cells. This represents a promising therapy regime that can be fast-tracked to tackle TP53-mutant blood cancers in the clinic.

Keywords
BH3-mimetic drugs; STING; acute myeloid leukemia; apoptosis; blood cancer; lymphoma; p53.
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