Putting the STING Back into BH3-Mimetic Drugs for TP53-Mutant Blood Cancers

Medicine Biochemistry Genetics Oncology Hematology Life Sciences
TP53 mutation blood cancer BH3-mimetic drugs STING agonists apoptosis anti-cancer therapy

Applying STING Function to BH3-Mimetic Drugs for Treating TP53 Mutant Blood Cancers

In the recently published article in Cancer Cell titled “Putting the sting back into BH3-mimetic drugs for TP53-mutant blood cancers,” Sarah T. Diepstraten and colleagues conducted in-depth research to explore how to enhance the efficacy of BH3-mimetic drugs in TP53-mutant blood cancers. This study was conducted by a team from the Walter and Eliza Hall Institute of Medical Research (WEHI), in collaboration with the University of Melbourne, Peter MacCallum Cancer Centre, and the Royal Melbourne Hospital, and was published on May 13, 2024.

Background

Blood cancers with TP53 mutations, such as Acute Myeloid Leukemia (AML) and Non-Hodgkin Lymphoma (NHL), pose significant challenges in clinical treatment. Although BH3-mimetic drugs like venetoclax help inhibit anti-apoptotic protein BCL-2, thereby inducing apoptosis in cancer cells, malignant tumors with TP53 mutations respond poorly to this treatment, leading to a generally poor prognosis for patients. The aim of this study is to address this issue and explore how to increase the efficacy of BH3-mimetic drugs in TP53-mutant blood cancers.

Research Methods

Researchers discovered that under normal TP53 function, BH3-mimetic drug-induced mitochondrial outer membrane permeabilization (MOMP) can activate P53, thereby enhancing the expression of BH3-Only proteins and promoting the apoptosis process. However, in cancer cells with TP53 mutations, this positive feedback mechanism fails, resulting in poor treatment outcomes. Therefore, they proposed enhancing treatment efficacy by activating the cGAS/STING pathway, making the expression of BH3-Only proteins independent of P53.

The research team used various experimental models including TP53-mutant mouse lymphoma models, human NK/T-cell lymphoma, and acute myeloid leukemia cells to validate their findings. The key steps include:

  1. Cell and Drug Treatment: Pretreating cells with QVD-OPh before using BH3-mimetic drugs (to block downstream effects of apoptosis and purely study upstream mechanisms).

  2. Western Blot and Quantitative PCR: Detecting the expression of P53 and its downstream target genes such as NOXA, PUMA, and BIM to determine whether BH3-mimetic drugs activate the P53 pathway.

  3. CRISPR-Cas9 Gene Editing: Creating cell lines deficient in TP53, Bax/Bak, and STING to further clarify the roles of these genes in BH3-mimetic drug-mediated apoptosis.

  4. RNA Sequencing and Analysis: Comparing cells before and after treatment with RNA sequencing to understand the overall changes in gene expression and using Gene Set Enrichment Analysis (GSEA) to identify active signaling pathways.

  5. Combination Drug Therapy: Combining STING agonists with BH3-mimetic drugs to test their combined efficacy on TP53-mutant cells and determining the impact of this drug combination on cell survival through cell competition assays.

  6. In Vivo Experiments: Using Rag1-/- immunodeficient mice transplanted with lymphoma cells to observe the effect of combination drug therapy on tumor growth and mouse survival time.

Research Results

The research demonstrated that BH3-mimetic drug-induced MOMP activated P53, thereby enhancing the expression of BH3-Only proteins. This positive feedback mechanism fails in TP53-mutant cancer cells, significantly reducing treatment efficacy. However, by using STING agonists like ADU-S100 or DIABZI, the expression levels of BH3-Only proteins were greatly increased independently of P53, thus enhancing apoptotic signaling. This finding was validated not only in mouse models but also in human malignant tumor cell lines.

Experiments targeting TP53-mutant mouse lymphoma cells, human NK/T-cell lymphoma, and acute myeloid leukemia cells showed that combination therapy with STING agonists and BH3-mimetic drugs significantly enhanced cell-killing effects and reduced the risk of drug resistance. These results lay the foundation for the rapid clinical application of this combination therapy in the future.

Conclusion

This study elucidated the role of P53 in BH3-mimetic drug-induced apoptosis and identified that activating the cGAS/STING pathway can enhance the expression of BH3-Only proteins independently of P53. The study proposed an innovative combination therapy of STING agonists and BH3-mimetic drugs. This approach is particularly suitable for patients with malignant TP53-mutant blood cancers and holds significant clinical potential.

Highlights

  1. Innovative Mechanism: This study for the first time revealed a positive feedback mechanism where P53 is involved in BH3-mimetic drug-induced apoptosis.
  2. Combination Therapy: Proposed a combination therapy of STING agonists and BH3-mimetic drugs, showing significant efficacy in patients with TP53-mutant blood cancers.
  3. Clinical Potential: Given that the involved drugs are already in clinical trials or use, these results are expected to quickly translate into clinical treatment protocols.

Significance and Value

This research not only provides a new treatment strategy for patients with TP53-mutant blood cancers but also offers a new perspective for further understanding the tumor-suppressive function of P53. It revealed the potential application of BH3-mimetic drugs and the STING pathway in cancer treatment. These findings hold significant scientific and clinical implications and are expected to profoundly influence the formulation of future therapeutic strategies for malignant blood cancers.