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

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

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
Free article

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

Sarah T Diepstraten et al. Cancer Cell. .
Free article

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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Conflict of interest statement

Declaration of interests All authors are employees of WEHI which receives milestone and royalty payments related to venetoclax. A.S., A.H.W., and G.L.K. have in the past received research funding from Servier for work on the development of MCL-1 inhibitors. A.W.R. has previously received research funding from AbbVie and is an inventor on a patent related to venetoclax dosing. A.H.W. has received research funding from AbbVie and consulting fees from AbbVie for clinical trials related to venetoclax. We have submitted a provisional patent application to cover the rationale of the described drug combination (STING agonists alongside BH3-mimetics).

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