2. Academic Validation
  3. SOX2 expression in prostate cancer drives resistance to nuclear hormone receptor signaling inhibition through the WEE1/CDK1 signaling axis

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

  • Cancer Lett. 2023 May 9;216209. doi: 10.1016/j.canlet.2023.216209.
Anthony Williams 1,  Lisa Gutgesell 2,  Larischa de Wet 2,  Phillip Selman 1,  Arunangsu Dey 1,  Mahati Avineni 1,  Isha Kapoor 1,  Megan Mendez 1,  Ryan Brown 2,  Sophia Lamperis 3,  Chuck Blajszczak 1,  Eric Bueter 4,  Steve Kregel 5,  Donald J Vander Griend 2,  Russell Szmulewitz 6
Affiliations

Affiliations

  • 1 Department of Medicine, Section of Hematology & Oncology, The University of Chicago Medical Center, 5841 S Maryland Avenue, Chicago, IL, 60637, USA.
  • 2 Department of Pathology, University of Illinois at Chicago, 909 S Wolcott Avenue, Chicago, IL, 60612, USA.
  • 3 Department of Medicine, Section of Hematology and Oncology, Northwestern University - Feinberg School of Medicine, 420 E Superior St, Chicago, IL, 60611, USA.
  • 4 Department of Medicine, Section of Hematology & Oncology, The University of Chicago Medical Center, 5841 S Maryland Avenue, Chicago, IL, 60637, USA; Committee on Cancer Biology, The University of Chicago Medical Center, 5841 S Maryland Avenue, Chicago, IL, 60637, USA.
  • 5 Department of Cancer Biology, Loyola University - Cardinal Bernardin Cancer Center, 2160 S 1st Ave, Maywood, IL, 60153, USA.
  • 6 Department of Medicine, Section of Hematology & Oncology, The University of Chicago Medical Center, 5841 S Maryland Avenue, Chicago, IL, 60637, USA. Electronic address: rszmulew@medicine.bsd.uchicago.edu.
PMID: 37169162 DOI: 10.1016/j.canlet.2023.216209
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.

Keywords

AR; CDK1; Drug resistance; GR; SOX2; WEE1.

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