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

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posted on 2024-05-21, 01:10 authored by Sarah DiepstratenSarah Diepstraten, Y Yuan, John La-MarcaJohn La-Marca, S Young, C Chang, L Whelan, AM Ross, KC Fischer, G Pomilio, R Morris, A Georgiou, V Litalien, FC Brown, AW Roberts, A Strasser, AH Wei, GL Kelly

Summary: 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.

Funding

This study was supported by the Australian Government NHMRC (GNT1113133 [A.S.], GNT1116937 [A.S.], GNT2018071 [A.H.W.], GNT2002618 [G.L.K.], GNT2001201 [G.L.K.], GNT2011139 [G.L.K., A.W.R., and A.H.W.], GNT2010275 [A.S.], GNT1176175 [F.C.B.], GNT1174902 [A.W.R.], and GNT2014234 [Y.Y.]), Victorian Cancer Agency (17028 [G.L.K.] and 21006 [S.T.D.]), MRFF (2023403 [A.H.W.]), CASS Foundation (S.T.D. and J.E.L.M.), estate of Anthony (Toni) Redstone OAM (A.S. and G.L.K.), Craig Perkins Cancer Research Foundation (G.L.K.), Dyson Bequest (G.L.K.), Harry Secomb Foundation (G.L.K.), Robert and Janette Boffey (J.E.L.M.), Jill and Stuart Bales (S.T.D.), Metcalf Family Fellowship (A.H.W.), RCPA Foundation (Y.Y), and the Victorian State Government Operational Infrastructure Support and NHMRC Independent Research Institute Infrastructure Support schemes.

History

Publication Date

2024-05-13

Journal

Cancer Cell

Volume

42

Issue

5

Pagination

28p. (p. 850-868.e9)

Publisher

Elsevier

ISSN

1535-6108

Rights Statement

© 2024 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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