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

Chaoyun Pan, Ji Hoon 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, Sumin Kang

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

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.

Original languageEnglish (US)
Article number4960
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 1 2021
Externally publishedYes

ASJC Scopus subject areas

  • General Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • General Physics and Astronomy

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