In a groundbreaking advancement for acute myeloid leukemia (AML) treatment, researchers have uncovered a promising combination therapy that holds the potential to surmount chemotherapy resistance—one of the biggest obstacles in effective cancer management. This study highlights the synergistic effects of Venetoclax, a known BCL-2 inhibitor, combined with ML385, an inhibitor of the nuclear factor erythroid 2-related factor 2 (Nrf2), revealing new therapeutic avenues by targeting oxidative stress pathways pivotal to AML cell survival.
Acute myeloid leukemia, characterized by the rapid proliferation of dysfunctional myeloid cells in the bone marrow, often develops resistance to conventional chemotherapy regimens. This resistance stymies treatment efficacy, leading to poor prognoses and limited long-term survival. The study, conducted by Zhao et al., delves into the molecular underpinnings that allow AML cells to endure chemotherapeutic assaults, positioning oxidative stress regulation via the Nrf2/ARE pathway as a key player in mediating this resistance.
Venetoclax, an FDA-approved agent, targets the anti-apoptotic protein BCL-2, thereby promoting programmed cell death in leukemia cells. Despite its initial efficacy, resistance emerges, diminishing its therapeutic benefit. Addressing this challenge, the research introduces ML385, a selective inhibitor of Nrf2 that suppresses antioxidant response element (ARE)-driven gene expression, effectively dismantling the AML cells’ defense mechanisms against oxidative damage.
Oxidative stress has long been recognized as a double-edged sword in cancer biology. While excessive reactive oxygen species (ROS) can induce cytotoxicity and apoptosis, cancer cells often exploit antioxidant pathways, mediated by Nrf2, to mitigate ROS and survive under oxidative duress. By inhibiting Nrf2, ML385 compromises AML cells’ antioxidant defenses, rendering them vulnerable to oxidative stress and apoptosis, particularly when combined with Venetoclax’s pro-apoptotic effects.
The comprehensive investigation revealed that the combination therapy significantly reduced viability of AML cells that were previously resistant to chemotherapy. This effect is attributable to the downregulation of Nrf2 and its downstream targets, leading to an accumulation of intracellular ROS. This oxidative overload tips the balance towards cell death, a strategy that could potentially be generalized to other malignancies exhibiting similar resistance mechanisms.
Beyond cellular assays, the research incorporated in vivo models that corroborated the enhanced antileukemic activity of Venetoclax and ML385 co-administration. Treated subjects exhibited marked reductions in leukemic burden and improved survival outcomes without notable increases in toxicity, underscoring the therapeutic promise and tolerability of this approach.
One intriguing facet of this study lies in its elucidation of the molecular crosstalk between apoptotic pathways and oxidative stress regulation. The data suggest that targeting Nrf2 not only sensitizes AML cells to oxidative damage but may also enhance the intrinsic apoptotic pathways modulated by Venetoclax, creating a multi-pronged attack on leukemia cells.
The implications of this research extend far beyond the immediate clinical application for AML. Given the central role of oxidative stress and Nrf2 in a myriad of cancers and chemoresistance phenotypes, ML385 or similar agents could redefine resistance management and improve outcomes in diverse oncological contexts.
Importantly, this study opens discourse on the customization of cancer therapies based on molecular vulnerabilities, advocating for integrative treatment modalities that combine direct cell death induction with metabolic and oxidative modulation.
While these findings are promising, the transition from bench to bedside necessitates rigorous clinical trials to evaluate efficacy, safety, dosing strategies, and potential resistance mechanisms that could emerge with combined Venetoclax and ML385 treatment.
Moreover, the study prompts further exploration into biomarkers predictive of Nrf2 pathway activation in AML patients, enabling precision medicine approaches tailored to individual tumor biology and resistance profiles.
The utilization of ML385 also invites consideration of its pharmacodynamic and pharmacokinetic properties, potential off-target effects, and compatibility with existing chemotherapeutics to optimize its integration into standard care protocols.
This research represents a vital stride in overcoming the persistent challenge of chemotherapy resistance in AML, showcasing the power of targeted pathway inhibition combined with apoptotic induction to dismantle cancer cell defenses.
In conclusion, the study by Zhao et al. offers a compelling paradigm shift in AML treatment strategies by leveraging the vulnerabilities associated with oxidative stress regulation. By combining Venetoclax with ML385, there is renewed hope for overcoming resistance and achieving more durable remissions in this aggressive hematological malignancy.
As the oncology community continues to unravel the intricate molecular pathways involved in cancer persistence and resistance, these findings herald a new era of combination therapies designed not just to kill cancer cells, but to dismantle their survival networks from multiple angles simultaneously.
This innovative approach is not only scientifically elegant but also clinically imperative, promising to enhance the effectiveness of existing drugs and ultimately improve patient outcomes in a disease area with significant unmet needs.
Subject of Research: Therapeutic strategy combining Venetoclax with ML385 to overcome chemotherapy resistance in acute myeloid leukemia via modulation of Nrf2/ARE-mediated oxidative stress.
Article Title: Venetoclax combined with ML385 overcomes chemotherapy resistance in acute myeloid leukemia by modulating Nrf2/ARE-mediated oxidative stress.
Article References:
Zhao, L., Guo, Y., Jian, J. et al. Venetoclax combined with ML385 overcomes chemotherapy resistance in acute myeloid leukemia by modulating Nrf2/ARE-mediated oxidative stress. Med Oncol 43, 114 (2026). https://doi.org/10.1007/s12032-025-03229-8
Image Credits: AI Generated
DOI: https://doi.org/10.1007/s12032-025-03229-8
Tags: acute myeloid leukemia treatmentBCL-2 inhibition therapycancer management advancementsML385 Nrf2 inhibitornew therapeutic avenues for leukemiaNrf2 ARE pathway in cancerovercoming chemotherapy resistanceoxidative stress in AMLprogrammed cell death inductionsynergistic effects in leukemiatargeted therapy for AMLVenetoclax chemotherapy resistance
