Cisplatin-mediated activation of glucocorticoid receptor induces platinum resistance via MAST1

Chaoyun Pan, JiHoon Kang, Jung Seok Hwang, Jie Li, Austin C. Boese, Xu Wang, Likun Yang, Titus J. Boggon, Georgia Z. Chen, Nabil F. Saba, Dong M. Shin, Kelly R. Magliocca, Lingtao Jin and Sumin Kang ()
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Chaoyun Pan: Sun Yat-sen University
JiHoon Kang: Emory University School of Medicine
Jung Seok Hwang: Emory University School of Medicine
Jie Li: Emory University School of Medicine
Austin C. Boese: Emory University School of Medicine
Xu Wang: Emory University School of Medicine
Likun Yang: Emory University School of Medicine
Titus J. Boggon: Yale University School of Medicine
Georgia Z. Chen: Emory University School of Medicine
Nabil F. Saba: Emory University School of Medicine
Dong M. Shin: Emory University School of Medicine
Kelly R. Magliocca: Emory University School of Medicine
Lingtao Jin: University of Florida, College of Medicine
Sumin Kang: Emory University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Agonists of glucocorticoid receptor (GR) are frequently given to cancer patients with platinum-containing chemotherapy to reduce inflammation, but how GR influences tumor growth in response to platinum-based chemotherapy such as cisplatin through inflammation-independent signaling remains largely unclear. Combined genomics and transcription factor profiling reveal that MAST1, a critical platinum resistance factor that reprograms the MAPK pathway, is upregulated upon cisplatin exposure through activated transcription factor GR. Mechanistically, cisplatin binds to C622 in GR and recruits GR to the nucleus for its activation, which induces MAST1 expression and consequently reactivates MEK signaling. GR nuclear translocation and MAST1 upregulation coordinately occur in patient tumors collected after platinum treatment, and align with patient treatment resistance. Co-treatment with dexamethasone and cisplatin restores cisplatin-resistant tumor growth, whereas addition of the MAST1 inhibitor lestaurtinib abrogates tumor growth while preserving the inhibitory effect of dexamethasone on inflammation in vivo. These findings not only provide insights into the underlying mechanism of GR in cisplatin resistance but also offer an effective alternative therapeutic strategy to improve the clinical outcome of patients receiving platinum-based chemotherapy with GR agonists.

Date: 2021
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DOI: 10.1038/s41467-021-24845-8

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