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Modulating MGMT expression through interfering with cell signaling pathways

Peiying Bai¹, Tengjiao Fan², Xin Wang³

¹Beijing Key Laboratory of Environmental and Viral Oncology, Faculty of Environment and Life, Beijing University of Technology, Beijing 100124, China.

Biochemical Pharmacology

|July 31, 2023

Abstract:

Guanine O⁶-alkylating agents are widely used as first-line chemotherapeutic drugs due to their ability to induce cytotoxic DNA damage. However, a major hurdle in their effectiveness is the emergence of chemoresistance, largely attributed to the DNA repair pathway mediated by O⁶-methylguanine-DNA methyltransferase (MGMT). MGMT plays an important role in removing the alkyl groups from lethal O⁶-alkylguanine (O⁶-AlkylG) adducts formed by chemotherapeutic alkylating agents. By doing so, MGMT enables tumor cells to evade apoptosis and develop drug resistance toward DNA alkylating agents. Although covalent inhibitors of MGMT, such as O⁶-benzylguanine (O⁶-BG) and O⁶-(4-bromothenyl)guanine (O⁶-4-BTG or lomeguatrib), have been explored in clinical settings, their utility is limited due to severe delayed hematological toxicity observed in most patients when combined with alkylating agents. Therefore, there is an urgent need to identify new targets and unravel the underlying molecular mechanisms and to develop alternative therapeutic strategies that can overcome MGMT-mediated tumor resistance. In this context, the regulation of MGMT expression via interfering the specific cell signaling pathways (e.g., Wnt/β-catenin, NF-κB, Hedgehog, PI3K/AKT/mTOR, JAK/STAT) emerges as a promising strategy for overcoming tumor resistance, and ultimately enhancing the efficacy of DNA alkylating agents in chemotherapy.

Insights

Chemoresistance to DNA alkylating agents is often caused by O6-methylguanine-DNA methyltransferase (MGMT). Targeting MGMT expression through cell signaling pathways offers a promising strategy to enhance chemotherapy efficacy and overcome tumor resistance.

Area of Science:

Oncology
Molecular Biology
Pharmacology

Background:

Guanine O6-alkylating agents are crucial chemotherapeutics inducing DNA damage.
Tumor resistance to these agents is frequently mediated by O6-methylguanine-DNA methyltransferase (MGMT).
MGMT repairs lethal O6-alkylguanine adducts, enabling cancer cells to evade apoptosis and develop resistance.

Purpose of the Study:

To address the limitations of current MGMT inhibitors, such as O6-benzylguanine (O6-BG) and O6-(4-bromothenyl)guanine (O6-4-BTG), which cause significant toxicity.
To explore novel therapeutic strategies for overcoming MGMT-mediated chemoresistance.
To investigate the potential of targeting cell signaling pathways regulating MGMT expression.

Main Methods:

Review of existing literature on DNA alkylating agents, MGMT, and chemoresistance mechanisms.
Analysis of clinical data regarding the efficacy and toxicity of MGMT inhibitors.
Exploration of cell signaling pathways (Wnt/β-catenin, NF-κB, Hedgehog, PI3K/AKT/mTOR, JAK/STAT) involved in MGMT regulation.

Main Results:

O6-BG and O6-4-BTG show limited clinical utility due to severe delayed hematological toxicity.
MGMT's role in repairing DNA damage and conferring resistance is well-established.
Several cell signaling pathways are implicated in the regulation of MGMT expression.

Conclusions:

There is a critical need for alternative strategies to overcome MGMT-mediated chemoresistance.
Targeting the regulation of MGMT expression via specific cell signaling pathways presents a promising approach.
Interfering with these pathways could enhance the efficacy of DNA alkylating agents in chemotherapy.

Read full analysis

Keywords:

Alkylating agents Cell signaling pathways Cytotoxicity Inhibitors MGMT Tumor resistance

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