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

Cancer Lett. 2023 Jul 1:565:216209. doi: 10.1016/j.canlet.2023.216209. Epub 2023 May 9.


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.

Keywords: AR; CDK1; Drug Resistance; GR; Mitotic Catastrophe; SOX2; WEE1.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Androgen Receptor Antagonists / pharmacology
  • Antineoplastic Agents* / pharmacology
  • CDC2 Protein Kinase / genetics
  • CDC2 Protein Kinase / metabolism
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Humans
  • Male
  • Prostatic Neoplasms, Castration-Resistant* / drug therapy
  • Prostatic Neoplasms, Castration-Resistant* / genetics
  • Protein-Tyrosine Kinases / metabolism
  • Receptors, Cytoplasmic and Nuclear
  • SOXB1 Transcription Factors / genetics
  • Signal Transduction


  • CDC2 Protein Kinase
  • Antineoplastic Agents
  • Cell Cycle Proteins
  • Androgen Receptor Antagonists
  • Receptors, Cytoplasmic and Nuclear
  • WEE1 protein, human
  • Protein-Tyrosine Kinases
  • SOX2 protein, human
  • SOXB1 Transcription Factors
  • CDK1 protein, human