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

in Cancer cell by 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

TLDR

  • The study looked at how a protein called TP53 helps fight blood cancers. The study found that a type of drug called BH3-mimetic drugs work better when TP53 is present. The study also found that TP53 is activated in a special way when these drugs are used, which helps the drugs work even better. The study used a special type of drug called a STING agonist to help activate TP53 in this way. The study found that using these drugs together killed blood cancer cells very effectively. The study suggests that this combination of drugs could be used to treat TP53-mutant blood cancers in the clinic.

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.

Overview

  • The study investigates the role of TP53 in blood cancers and the effectiveness of BH3-mimetic drugs in inducing apoptosis. The study found that functional p53 is required for maximal cancer cell killing by BH3-mimetics through an unknown mechanism. The study also identified a feedforward loop that activates p53 following BH3-mimetic induced mitochondrial outer membrane permeabilization, leading to BH3-only protein induction and potentiating the pro-apoptotic signal. The study highlights the therapeutic barrier imposed by defects in TP53 and suggests that direct activation of the cGAS/STING pathway can overcome this barrier and promote apoptosis of blood cancer cells through p53-independent BH3-only protein upregulation. The study used clinically relevant STING agonists combined with BH3-mimetic drugs to efficiently kill TRP53/TP53-mutant mouse B lymphoma, human NK/T lymphoma, and acute myeloid leukemia cells, suggesting a promising therapy regime that can be fast-tracked to tackle TP53-mutant blood cancers in the clinic.

Comparative Analysis & Findings

  • The study compared the outcomes observed under different experimental conditions or interventions, specifically the effect of BH3-mimetic drugs on blood cancer cells with and without functional p53. The study found that functional p53 is required for maximal cancer cell killing by BH3-mimetics. The study also identified a feedforward loop that activates p53 following BH3-mimetic induced mitochondrial outer membrane permeabilization, leading to BH3-only protein induction and potentiating the pro-apoptotic signal. The study highlights the therapeutic barrier imposed by defects in TP53 and suggests that direct activation of the cGAS/STING pathway can overcome this barrier and promote apoptosis of blood cancer cells through p53-independent BH3-only protein upregulation. The study used clinically relevant STING agonists combined with BH3-mimetic drugs to efficiently kill TRP53/TP53-mutant mouse B lymphoma, human NK/T lymphoma, and acute myeloid leukemia cells, suggesting a promising therapy regime that can be fast-tracked to tackle TP53-mutant blood cancers in the clinic.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice. The study highlights the therapeutic barrier imposed by defects in TP53 and suggests that direct activation of the cGAS/STING pathway can overcome this barrier and promote apoptosis of blood cancer cells through p53-independent BH3-only protein upregulation. The study used clinically relevant STING agonists combined with BH3-mimetic drugs to efficiently kill TRP53/TP53-mutant mouse B lymphoma, human NK/T lymphoma, and acute myeloid leukemia cells, suggesting a promising therapy regime that can be fast-tracked to tackle TP53-mutant blood cancers in the clinic. The study also identifies limitations, such as the need for further research to understand the underlying mechanisms of the feedforward loop and the potential for off-target effects of STING agonists. Future research directions could include exploring the use of combination therapies that target multiple pathways, investigating the efficacy of BH3-mimetic drugs in combination with other chemotherapeutic agents, and studying the long-term effects of BH3-mimetic and STING agonist treatment on blood cancer patients.
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