Targeting Mitochondrial Transcription Sensitizes Acute Myeloid Leukemia Cells to BCL-2 Inhibition

Core Concepts

Inhibition of mitochondrial transcription by IMT sensitizes acute myeloid leukemia cells to the BCL-2 inhibitor venetoclax, leading to synergistic induction of apoptosis and suppression of oxidative phosphorylation.

Abstract

The content discusses a novel therapeutic strategy to target therapy-resistant acute myeloid leukemia (AML) by combining inhibition of mitochondrial transcription and BCL-2 inhibition.
Key highlights:

AML cells display increased reliance on oxidative phosphorylation (OXPHOS) for energy generation, making mitochondrial function a promising therapeutic target.
The inhibitor of mitochondrial transcription (IMT) specifically targets the mitochondrial RNA polymerase (POLRMT) and reduces transcription of mitochondrial DNA, impairing OXPHOS.
In vitro studies show that the combination of IMT and the BCL-2 inhibitor venetoclax synergistically inhibits cell proliferation, induces apoptosis, and suppresses OXPHOS in AML cell lines.
In AML cell-derived xenograft and patient-derived xenograft mouse models, the combination of IMT and venetoclax significantly delays leukemia progression and prolongs survival compared to single-agent treatments.
The combination therapy is effective even in venetoclax-resistant AML models, demonstrating that IMT can sensitize AML cells to other therapies.
The findings suggest that targeting mitochondrial transcription can be a promising strategy to overcome therapy resistance in AML.

Stats

Combination treatment with IMT and venetoclax significantly inhibits oxygen consumption rate (OXPHOS) in sensitive AML cell lines (MV4-11 and MOLM-13), but not in resistant THP-1 cells.
Combination treatment with IMT and venetoclax significantly reduces the proportion of human CD45+ leukemic cells in the peripheral blood, bone marrow, and spleen of AML patient-derived xenograft mouse models.

Quotes

"Combination treatment significantly enhances apoptosis induction in AML cell lines."
"Combination of IMT and venetoclax synergistically delays leukemia initiation in cell-derived leukemia mouse models."
"Combination of IMT and venetoclax synergistically decreases the tumor burden and increase the life span in an AML-PDX mouse model resistant to venetoclax."

Key Insights Distilled From

Reduced mitochondrial transcription sensitizes acute myeloid leukemia cells to BCL-2 inhibition

by Arabanian,L.... at www.biorxiv.org 09-25-2022

https://www.biorxiv.org/content/10.1101/2022.09.23.509145v2

Deeper Inquiries

How could the combination therapy of IMT and venetoclax be further optimized to improve efficacy and tolerability in AML patients?

To optimize the combination therapy of IMT and venetoclax for AML patients, several strategies can be considered:

Dose Optimization: Conducting dose-response studies to determine the most effective and tolerable doses of IMT and venetoclax in combination. This can help maximize the synergistic effects of the two compounds while minimizing potential side effects.

Treatment Schedule: Exploring different treatment schedules, such as alternating dosing regimens or intermittent therapy, to prevent the development of resistance and improve long-term efficacy.

Patient Stratification: Implementing patient stratification based on genetic markers or other biomarkers to identify individuals who are most likely to benefit from the combination therapy. This personalized approach can enhance treatment outcomes.

Combination with Other Therapies: Investigating the potential synergies of IMT and venetoclax with other targeted therapies or standard chemotherapy agents to create more comprehensive treatment regimens.

Mechanism of Action Studies: Further elucidating the molecular mechanisms underlying the synergistic effects of IMT and venetoclax to identify additional targets for combination therapy and potential biomarkers for treatment response.

Clinical Trials: Conducting well-designed clinical trials with a focus on efficacy, safety, and tolerability to validate the benefits of the combination therapy in AML patients and potentially refine the treatment protocol based on real-world data.

How could the combination therapy of IMT and venetoclax be further optimized to improve efficacy and tolerability in AML patients?

Resistance to the synergistic effects of IMT and venetoclax in TP53 mutant AML cells can be attributed to several potential mechanisms:

Altered Apoptotic Pathways: TP53 mutations can disrupt the normal apoptotic pathways, leading to decreased sensitivity to BCL-2 inhibition by venetoclax. This alteration in apoptotic signaling can reduce the effectiveness of the combination therapy.

Upregulation of Alternative Survival Pathways: TP53 mutant AML cells may upregulate alternative survival pathways, such as increased expression of anti-apoptotic proteins like MCL1 or BCL2L1, which can counteract the pro-apoptotic effects of venetoclax and IMT.

Metabolic Adaptations: TP53 mutations can drive metabolic adaptations in AML cells, leading to increased reliance on OXPHOS for energy production. This metabolic shift can provide a survival advantage to the cells, making them less susceptible to mitochondrial-targeting therapies like IMT.

TP53-Mediated DNA Repair Mechanisms: TP53 plays a crucial role in DNA repair mechanisms, and mutations in TP53 can lead to enhanced DNA repair capacity in AML cells. This increased DNA repair ability can contribute to resistance against the cytotoxic effects of the combination therapy.

Heterogeneity of TP53 Mutant Cells: TP53 mutant AML cells are known to exhibit heterogeneity, with subpopulations of cells displaying different levels of resistance mechanisms. This heterogeneity can contribute to the overall resistance of the cell population to IMT and venetoclax.

Could the targeting of mitochondrial transcription be a viable strategy for treating other types of therapy-resistant cancers beyond AML?

Yes, targeting mitochondrial transcription could be a viable strategy for treating other types of therapy-resistant cancers beyond AML. Some potential reasons include:

Common Dependence on OXPHOS: Many cancer types, not just AML, exhibit a high dependency on oxidative phosphorylation for energy production. Inhibiting mitochondrial transcription can disrupt OXPHOS and induce cell death in a broad range of cancer cells that rely on this metabolic pathway.

Mitochondrial Dysfunction in Cancer: Mitochondrial dysfunction is a hallmark of cancer cells, and targeting mitochondrial transcription can exploit this vulnerability to selectively kill cancer cells while sparing normal cells.

Synergistic Effects with Other Therapies: Combining mitochondrial transcription inhibitors with other targeted therapies or standard chemotherapies can enhance treatment efficacy and overcome resistance mechanisms in various cancer types.

Personalized Medicine Approaches: By identifying specific genetic or metabolic vulnerabilities in different cancer types, the targeting of mitochondrial transcription can be tailored to individual patients, leading to more effective and personalized treatment strategies.

Preclinical Evidence: Preclinical studies in various cancer models have shown promising results with mitochondrial transcription inhibitors, indicating the potential for broader applications beyond AML. Further research and clinical trials are needed to validate these findings in other cancer types.