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| Status |
Public on Apr 25, 2024 |
| Title |
Putting the STING back into BH3-mimetic drugs for TP53 mutant blood cancers |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
TP53-mutant blood cancers remain a major clinical challenge. BH3-mimetic drugs inhibit BCL-2 pro-survival proteins to promote cancer cell apoptosis. Despite acting downstream of TP53, functional TP53 is required for maximal cancer cell killing by BH3-mimetics through an unknown mechanism. Here, we report TP53 can be activated following BH3-mimetic induced mitochondrial outer membrane permeabilization, which leads to induction of BH3-only proteins, thereby potentiating the pro-apoptotic signal. TP53-deficient lymphomas lack this feed-forward loop, providing opportunities for survival and disease relapse after BH3-mimetic treatment. The therapeutic barrier imposed by defects in TP53 could be overcome by direct activation of the cGAS/STING pathway, which promotes apoptosis of blood cancer cells through TP53-independent BH3-only protein upregulation. Combining clinically relevant STING agonists with BH3-mimetics efficiently killed 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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| Overall design |
To examine the downstream efffects of apoptosis-inducing drugs, mouse Eu-Myc lymphoma cells were treated with the MCL-1 inhibitor S63845 and/or the STING agonist diABZI for 24 h in the presence of caspase inhibitors and RNAseq performed. For STING agonist comparisons, 2 independent Eu-Myc lymphoma cell lines were included. For MCL-1 inhibitor (S63845) comparisons, 3 independent Eu-Myc lymphoma cell lines were included. The study includes parental lymphomas (control, containing Cas9 and a non-targeting sgRNA (hBim)), as well as Trp53 KO and Sting KO derivatives, generated by CRISPR/Cas9.
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| Contributor(s) |
Diepstraten ST, La Marca JE, Kelly GL |
| Citation missing |
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| Submission date |
Mar 12, 2024 |
| Last update date |
Apr 25, 2024 |
| Contact name |
Sarah T Diepstraten |
| E-mail(s) |
diepstraten.s@wehi.edu.au
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| Organization name |
The Walter and Eliza Hall Institute
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| Street address |
1G Royal Pde
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| City |
Parkville |
| State/province |
VIC |
| ZIP/Postal code |
3052 |
| Country |
Australia |
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| Platforms (1) |
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| Samples (28)
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| Relations |
| BioProject |
PRJNA1086799 |
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