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Ferroptosis as a therapeutic vulnerability in ARID1A-deficient bladder cancer
Mengxue Zhao1, Xuefeng Wang1, Xianbin Duan1
1Yunnan Key Laboratory of Cell Metabolism and Disease, and Center for Life Sciences, School of Life Sciences, Yunnan University, Kunming, China.
Abstract:
ARID1A is among the most frequently mutated genes in bladder cancer, yet no targeted therapy exists for this molecular subset. Here, we identify ferroptosis induction as a synthetic lethal strategy in ARID1A-deficient bladder cancer. We found that ARID1A loss impaired the NRF2-SLC7A11-glutathione (GSH) axis, leading to redox imbalance and profound sensitivity to the ferroptosis inducer RSL-3. In vitro, ARID1A knockdown depleted intracellular GSH and enhanced RSL-3-induced lipid peroxidation and cell death. Mechanistically, ARID1A directly regulated NRF2 transcription and its target SLC7A11, and restoring SLC7A11 or NRF2 activity or GSH levels rescued ferroptosis sensitivity. In vivo, RSL-3 treatment delayed tumor progression, reduced muscle invasion, and improved survival in two types of Arid1a -deficient mouse models. Furthermore, patient-derived organoids from ARID1A-low human tumors exhibited heightened RSL-3 sensitivity rather than ARID1A-high tumor. Our findings establish ferroptosis as a targetable vulnerability in ARID1A-deficient bladder cancer and provide a compelling rationale for clinical translation of ferroptosis-based therapies in this molecularly defined population.
Insights
Targeting ferroptosis offers a new therapeutic strategy for ARID1A-deficient bladder cancer. This approach exploits synthetic lethality by impairing the NRF2-SLC7A11-glutathione axis, leading to cancer cell death.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- ARID1A mutations are common in bladder cancer, lacking targeted therapies.
- Understanding ARID1A's role is crucial for developing new treatment strategies.
Purpose of the Study:
- To identify a synthetic lethal strategy for ARID1A-deficient bladder cancer.
- To investigate the potential of ferroptosis induction as a therapeutic approach.
Main Methods:
- Utilized in vitro knockdown models and in vivo mouse models.
- Assessed ferroptosis induction via RSL-3 treatment.
- Analyzed the NRF2-SLC7A11-glutathione axis and ARID1A's regulatory role.
- Tested sensitivity in patient-derived organoids.
Main Results:
- ARID1A loss impairs the NRF2-SLC7A11-glutathione axis, increasing ferroptosis sensitivity.
- RSL-3 treatment showed efficacy in preclinical models (in vitro and in vivo).
- ARID1A-low human bladder tumors were more sensitive to RSL-3.
Conclusions:
- Ferroptosis is a targetable vulnerability in ARID1A-deficient bladder cancer.
- Ferroptosis-based therapies show promise for this patient population.
- Findings support clinical translation of ferroptosis inducers.
