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Putting the STING back into BH3-mimetic drugs for TP53-mutant blood cancers.
Diepstraten, Sarah T; Yuan, Yin; La Marca, John E; Young, Savannah; Chang, Catherine; Whelan, Lauren; Ross, Aisling M; Fischer, Karla C; Pomilio, Giovanna; Morris, Rhiannon; Georgiou, Angela; Litalien, Veronique; Brown, Fiona C; Roberts, Andrew W; Strasser, Andreas; Wei, Andrew H; Kelly, Gemma L.
Afiliación
  • Diepstraten ST; 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: diepstraten.s@wehi.edu.au.
  • Yuan Y; 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 Melbourn
  • La Marca JE; 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
  • Young S; Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Chang C; Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Whelan L; Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Ross AM; 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.
  • Fischer KC; 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.
  • Pomilio G; Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Morris R; 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.
  • Georgiou A; Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Litalien V; Blood Cells and Blood Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
  • Brown FC; 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, Austra
  • Roberts AW; 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 Melbourn
  • Strasser A; 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.
  • Wei AH; 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 Melbourn
  • Kelly GL; 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: gkelly@wehi.edu.au.
Cancer Cell ; 42(5): 850-868.e9, 2024 May 13.
Article en En | MEDLINE | ID: mdl-38670091
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína p53 Supresora de Tumor / Apoptosis / Proteínas de la Membrana Límite: Animals / Humans Idioma: En Revista: Cancer Cell Asunto de la revista: NEOPLASIAS Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteína p53 Supresora de Tumor / Apoptosis / Proteínas de la Membrana Límite: Animals / Humans Idioma: En Revista: Cancer Cell Asunto de la revista: NEOPLASIAS Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos