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

Sarah T Diepstraten; Yin Yuan; John E La Marca; Savannah Young; Catherine Chang; Lauren Whelan; Aisling M Ross; Karla C Fischer; Giovanna Pomilio; Rhiannon Morris; Angela Georgiou; Veronique Litalien; Fiona C Brown; Andrew W Roberts; Andreas Strasser; Andrew H Wei; Gemma L Kelly

doi:10.1016/j.ccell.2024.04.004

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

Cancer Cell. 2024 May 13;42(5):850-868.e9. doi: 10.1016/j.ccell.2024.04.004. Epub 2024 Apr 25.

Authors

Sarah T Diepstraten¹, Yin Yuan², John E La Marca³, Savannah Young⁴, Catherine Chang⁴, Lauren Whelan⁴, Aisling M Ross⁵, Karla C Fischer⁶, Giovanna Pomilio⁴, Rhiannon Morris⁶, Angela Georgiou⁴, Veronique Litalien⁴, Fiona C Brown⁷, Andrew W Roberts², Andreas Strasser⁶, Andrew H Wei², Gemma L Kelly⁸

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.

MeSH terms

Animals
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Apoptosis* / drug effects
Cell Line, Tumor
Hematologic Neoplasms / drug therapy
Hematologic Neoplasms / genetics
Humans
Membrane Proteins* / genetics
Mice
Mutation
Peptide Fragments / pharmacology
Proto-Oncogene Proteins / genetics
Proto-Oncogene Proteins c-bcl-2 / genetics
Signal Transduction / drug effects
Tumor Suppressor Protein p53* / genetics