SOX2 expression in prostate cancer drives resistance to nuclear hormone receptor signaling inhibition through the WEE1/CDK1 signaling axis

Anthony Williams, Lisa Gutgesell, Larischa de Wet, Phillip Selman, Arunangsu Dey, Mahati Avineni, Isha Kapoor, Megan Mendez, Ryan Brown, Sophia Lamperis, Chuck Blajszczak, Eric Bueter, Steven Kregel, Donald J. Vander Griend, Russell Z. Szmulewitz

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

The development of androgen receptor signaling inhibitor (ARSI) drug resistance in prostate cancer (PC) remains therapeutically challenging. Our group has described the role of sex determining region Y-box 2 (SOX2) overexpression in ARSI-resistant PC. Continuing this work, we report that NR3C1, the gene encoding glucocorticoid receptor (GR), is a novel SOX2 target in PC, positively regulating its expression. Similar to ARSI treatment, SOX2-positive PC cells are insensitive to GR signaling inhibition using a GR modulating therapy. To understand SOX2-mediated nuclear hormone receptor signaling inhibitor (NHRSI) insensitivity, we performed RNA-seq in SOX2-positive and -negative PC cells following NHRSI treatment. RNA-seq prioritized differentially regulated genes mediating the cell cycle, including G2 checkpoint WEE1 Kinase (WEE1) and cyclin-dependent kinase 1 (CDK1). Additionally, WEE1 and CDK1 were differentially expressed in PC patient tumors dichotomized by high vs low SOX2 gene expression. Importantly, pharmacological targeting of WEE1 (WEE1i) in combination with an ARSI or GR modulator re-sensitizes SOX2-positive PC cells to nuclear hormone receptor signaling inhibition in vitro, and WEE1i combined with ARSI significantly slowed tumor growth in vivo. Collectively, our data suggest SOX2 predicts NHRSI resistance, and simultaneously indicates the addition of WEE1i to improve therapeutic efficacy of NHRSIs in SOX2-positive PC.

Original languageEnglish
Article number216209
JournalCancer Letters
Volume565
DOIs
StatePublished - Jul 1 2023

Keywords

  • AR
  • CDK1
  • Drug Resistance
  • GR
  • Mitotic Catastrophe
  • SOX2
  • WEE1

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