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AZD1775 synergizes with SLC7A11 inhibition to promote ferroptosis
Chen Xiong1,2, Hong Ling2,3, Yingdan Huang1,2
1Fudan University Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, China.
Abstract:
Tumor suppressor p53-mediated cell cycle arrest and DNA damage repair may exert cytoprotective effects against cancer therapies, including WEE1 inhibition. Considering that p53 activation can also lead to multiple types of cell death, the role of this tumor suppressor in WEE1 inhibitor-based therapies remains disputed. In this study, we reported that nucleolar stress-mediated p53 activation enhanced the WEE1 inhibitor AZD1775-induced ferroptosis to suppress lung cancer growth. Our findings showed that AZD1775 promoted ferroptosis by blocking cystine uptake, an action similar to that of Erastin. Meanwhile, inhibition of WEE1 by the WEE1 inhibitors or siRNAs induced compensatory upregulation of SLC7A11, which conferred resistance to ferroptosis. Mechanistically, AZD1775 prevented the enrichment of H3K9me3, a histone marker of transcriptional repression, on the SLC7A11 promoter by repressing the expression of the histone methyltransferase SETDB1, thereby enhancing NRF2-mediated SLC7A11 transcription. This finding was also validated using the H3K9me3 inhibitor BRD4770. Remarkably, we found that the nucleolar stress-inducing agent Actinomycin D (Act. D) inhibited SLC7A11 expression by activating p53, thus augmenting AZD1775-induced ferroptosis. Moreover, the combination of AZD1775 and Act. D synergistically suppressed wild-type p53-harboring lung cancer cell growth both in vitro and in vivo. Altogether, our study demonstrates that AZD1775 promotes ferroptosis by targeting cystine uptake but also mediates the adaptive activation of SLC7A11 through the WEE1-SETDB1 cascade and NRF2-induced transcription, and inhibition of SLC7A11 by Act. D boosts the anti-tumor efficacy of AZD1775 by enhancing ferroptosis in cancers with wild-type p53.
Insights
WEE1 inhibitor AZD1775 induces ferroptosis in lung cancer by blocking cystine uptake. Combining AZD1775 with Actinomycin D enhances this effect by inhibiting SLC7A11, suppressing tumor growth in p53-wildtype cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapy
Background:
- The role of tumor suppressor p53 in cancer therapy response, particularly WEE1 inhibition, is complex due to its dual role in cell cycle arrest and cell death.
- WEE1 inhibitors are a promising cancer therapy, but understanding their interaction with p53 pathways is crucial for optimizing efficacy.
Purpose of the Study:
- To investigate the role of p53 activation in WEE1 inhibitor-induced ferroptosis and its potential to suppress lung cancer growth.
- To elucidate the molecular mechanisms by which WEE1 inhibition affects ferroptosis and to identify strategies to enhance WEE1 inhibitor efficacy.
Main Methods:
- Utilized WEE1 inhibitors (AZD1775) and siRNAs in lung cancer cell lines.
- Assessed ferroptosis induction by measuring cystine uptake and SLC7A11 expression.
- Investigated histone modifications (H3K9me3) and gene expression (SETDB1, SLC7A11, NRF2).
- Employed nucleolar stress-inducing agents (Actinomycin D) and validated findings in vitro and in vivo.
Main Results:
- AZD1775 induced ferroptosis by blocking cystine uptake, similar to Erastin.
- WEE1 inhibition led to compensatory SLC7A11 upregulation, conferring resistance to ferroptosis.
- AZD1775 repressed SETDB1, reducing H3K9me3 on the SLC7A11 promoter and enhancing NRF2-mediated transcription.
- Actinomycin D inhibited SLC7A11 via p53 activation, augmenting AZD1775-induced ferroptosis.
- Combination therapy synergistically suppressed wild-type p53 lung cancer growth.
Conclusions:
- AZD1775 promotes ferroptosis via cystine uptake inhibition and adaptive SLC7A11 activation through the WEE1-SETDB1-NRF2 pathway.
- Inhibiting SLC7A11 with Actinomycin D enhances AZD1775 efficacy by boosting ferroptosis in p53-wildtype lung cancers.
- This combination strategy offers a promising therapeutic approach for lung cancer treatment.
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