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

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	850-868.e9
Journal	Cancer Cell
Volume	42
Issue number	5
DOIs	https://doi.org/10.1016/j.ccell.2024.04.004
Publication status	Published - 13 May 2024
Externally published	Yes

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ccell.2024.04.004

Cite this

Diepstraten, S. T., Yuan, Y., La Marca, J. E., Young, S., Chang, C., Whelan, L., Ross, A. M., Fischer, K. C., Pomilio, G., Morris, R., Georgiou, A., Litalien, V., Brown, F. C., Roberts, A. W., Strasser, A., Wei, A. H., & Kelly, G. L. (2024). Putting the STING back into BH3-mimetic drugs for TP53-mutant blood cancers. Cancer Cell, 42(5), 850-868.e9. https://doi.org/10.1016/j.ccell.2024.04.004

@article{39d4163a2e344b31bfa45a0e85bdb0d8,

title = "Putting the STING back into BH3-mimetic drugs for TP53-mutant blood cancers",

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",

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

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s)",

year = "2024",

month = may,

day = "13",

doi = "10.1016/j.ccell.2024.04.004",

language = "English",

volume = "42",

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Diepstraten, ST, Yuan, Y, La Marca, JE, Young, S, Chang, C, Whelan, L, Ross, AM, Fischer, KC, Pomilio, G, Morris, R, Georgiou, A, Litalien, V, Brown, FC, Roberts, AW, Strasser, A, Wei, AH & Kelly, GL 2024, 'Putting the STING back into BH3-mimetic drugs for TP53-mutant blood cancers', Cancer Cell, vol. 42, no. 5, pp. 850-868.e9. https://doi.org/10.1016/j.ccell.2024.04.004

TY - JOUR

T1 - Putting the STING back into BH3-mimetic drugs for TP53-mutant blood cancers

AU - Diepstraten, Sarah T.

AU - Yuan, Yin

AU - La Marca, John E.

AU - Young, Savannah

AU - Chang, Catherine

AU - Whelan, Lauren

AU - Ross, Aisling M.

AU - Fischer, Karla C.

AU - Pomilio, Giovanna

AU - Morris, Rhiannon

AU - Georgiou, Angela

AU - Litalien, Veronique

AU - Brown, Fiona C.

AU - Roberts, Andrew W.

AU - Strasser, Andreas

AU - Wei, Andrew H.

AU - Kelly, Gemma L.

PY - 2024/5/13

Y1 - 2024/5/13

N2 - 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.

AB - 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.

KW - BH3-mimetic drugs

KW - STING

KW - acute myeloid leukemia

KW - apoptosis

KW - blood cancer

KW - lymphoma

KW - p53

UR - http://www.scopus.com/inward/record.url?scp=85192248475&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2024.04.004

DO - 10.1016/j.ccell.2024.04.004

M3 - Article

C2 - 38670091

AN - SCOPUS:85192248475

SN - 1535-6108

VL - 42

SP - 850-868.e9

JO - Cancer Cell

JF - Cancer Cell

IS - 5

ER -

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

Abstract

Keywords

UN SDGs

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