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Revealing the Ferroptotic Phenotype of Medulloblastoma
Published on: March 15, 2024
BRG1-mediated suppression of ferroptosis underlies BTK inhibitor resistance
Soo-Yeon Hwang1, Xiangao Huang1,2, Helgi Nikolli1,3
1Department of Pathology and Laboratory Medicine, Weil Cornell Medicine, New York, NY, USA.
Abstract:
Resistance to Bruton's tyrosine kinase inhibitors (BTKi) remains a major therapeutic challenge in B-cell malignancies. Here, we identify chromatin remodeler BRG1-mediated suppression of ferroptosis as a central mechanism of BTKi resistance in mantle cell lymphoma (MCL), in which aberrant BRG1-dependent transcription program protects cells from BTKi-induced ferroptosis by restricting reactive oxygen species (ROS) and labile iron. Mechanistically, BRG1 promotes resistance through regulation of both BTK-dependent survival signaling and a BTK-independent transcriptional program. The latter is mediated by BRG1-driven induction of MEF2B, which upregulates atypical mitochondrial complex I subunit NDUFA4L2. Increased NDUFA4L2 restricts cellular respiration, preemptively limiting mitochondrial ROS generation and activating AMPK signaling, together reducing susceptibility to lipid peroxidation and ferroptosis. Pharmacologic inhibition of BRG1 disrupts these programs, restoring ferroptotic sensitivity and synergizing with BTKi across resistant MCL models. Together, our study establishes BRG1 as a central regulator of BTKi resistance and provides a rationale for co-targeting BRG1 and BTK as a therapeutic strategy for B-cell malignancies.
Insights
Chromatin remodeler BRG1 drives resistance to Bruton's tyrosine kinase inhibitors (BTKi) in B-cell cancers by suppressing ferroptosis. Inhibiting BRG1 restores sensitivity to BTKi, offering a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Bruton's tyrosine kinase inhibitors (BTKi) are crucial for treating B-cell malignancies but face resistance.
- Mechanisms underlying BTKi resistance, particularly in mantle cell lymphoma (MCL), require further elucidation.
Purpose of the Study:
- To identify key molecular mechanisms driving BTKi resistance in MCL.
- To explore the role of chromatin remodeling in conferring resistance to BTKi therapy.
Main Methods:
- Investigated the function of chromatin remodeler BRG1 in BTKi-resistant MCL models.
- Analyzed BRG1-dependent transcriptional programs impacting ferroptosis.
- Assessed the therapeutic potential of combined BRG1 and BTKi inhibition.
Main Results:
- BRG1 suppresses ferroptosis, a cell death pathway, thereby conferring BTKi resistance in MCL.
- BRG1 regulates both BTK-dependent and independent pathways, including MEF2B-NDUFA4L2 axis, to limit reactive oxygen species and labile iron.
- Pharmacologic inhibition of BRG1 restores ferroptosis sensitivity and synergizes with BTKi in resistant MCL models.
Conclusions:
- BRG1 is a central regulator of BTKi resistance in B-cell malignancies.
- Targeting BRG1 in combination with BTKi presents a promising therapeutic strategy for overcoming treatment resistance.
