Tumor Biology

SUN-277 - Resolving Physical and Functional Cooperation of SOX2 and FOXA1 in Therapy-Resistant Prostate Cancer

Sunday, June 14, 2026

9:00 AM - 4:00 PM CT

Location: ENDOExpo; Poster Floor

Abstract Poster Presenter(s)

John T. Phoenix, BS (he/him/his)

PhD Candidate
LOYOLA UNIVERSITY OF CHICAGO
Maywood, IL, United States

Co-Author(s)

AB

Audris Budreika, n/a

Department of Cancer Biology, Loyola University Chicago, Maywood, IL, USA
Maywood, Illinois, United States
DS

Devin A. Schmeck, n/a

Department of Medicine, University of Minnesota, Minneapolis, MN, USA
Minneapolis, Minnesota, United States
RK

Raymond J. Kostlan, n/a

Department of Cancer Biology, Loyola University Chicago, Maywood, IL, USA
Maywood, Illinois, United States
MF

Marina G. Ferrari, n/a

Department of Cancer Biology, Loyola University Chicago, Maywood, IL, USA
Maywood, Illinois, United States
CR

Charles S. Rogers, n/a

Department of Cancer Biology, Loyola University Chicago, Maywood, IL, USA
Maywood, Illinois, United States
KY

Kristen S. Young, n/a

LOYOLA UNIVERSITY OF CHICAGO
Maywood, Illinois, United States
CD

Carleen D. Deegan, n/a

Department of Cancer Biology, Loyola University Chicago, Maywood, IL, USA
Maywood, Illinois, United States
HB

Hannah E. Bergom, n/a

Department of Medicine, University of Minnesota, Minneapolis, MN, USA
Maywood, Illinois, United States
EB

Ella Boytim, n/a

Department of Medicine, University of Minnesota, Minneapolis, MN, USA
Minneapolis, Illinois, United States
RB

Ryan M. Brown, n/a

Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
Chicago, Illinois, United States
MB

Marcus W. Bienko, n/a

Department of Cancer Biology, Loyola University Chicago, Maywood, IL, USA
Maywood, Illinois, United States
JW

Julia A. Walewicz, n/a

Department of Cancer Biology, Loyola University Chicago, Maywood, IL, USA
Maywood, Illinois, United States
SB

Shreya K. Bhagi, n/a

Department of Cancer Biology, Loyola University Chicago, Maywood, IL, USA
Maywood, Illinois, United States
LE

Leigh Ellis, PhD

Center for Prostate Disease Research, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
Bethesda, Maryland, United States
EA

Emmanuel S. Antonarakis, MD

Department of Medicine, University of Minnesota, Minneapolis, MN, USA
Minneapolis, Minnesota, United States
JD

Justin M. Drake, PhD

Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA
Minneapolis, Minnesota, United States
PB

Pushpinder S. Bawa, PhD

Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA, USA
Boston, Massachusetts, United States
JV

Jordan E. Vellky, PhD

Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
Chicago, Illinois, United States
AW

Anthony Williams, PhD

Department of Medicine, University of Chicago, Chicago, IL, USA
Chicago, Illinois, United States
NR

Natalie M. Reizine, MD

Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
Chicago, Illinois, United States
JR

Jonathan P. Rennhack, PhD

Department of Cancer Biology, Loyola University Chicago, Maywood, IL, USA
Maywood, Illinois, United States
SF

Sean W. Fanning, PhD (he/him/his)

LOYOLA UNIVERSITY
Maywood, Illinois, United States
JH

Justin H. Hwang, PhD

Department of Medicine, University of Minnesota, Minneapolis, MN, USA
Minneapolis, Minnesota, United States
RS

Russell Z. Szmulewitz, MD

Department of Medicine, University of Chicago, Chicago, IL, USA
Chicago, Illinois, United States
DV

Donald J. Vander Griend, PhD

Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA
Chicago, Illinois, United States

Senior Author/Primary Investigator(s)

SK

Steven Kregel, PhD, MS (he/him/his)

Assistant Professor
Loyola University Chicago
Chicago, IL, United States

Disclosure(s):

John T. Phoenix, BS: No financial relationships to disclose

Steven Kregel, PhD, MS: No financial relationships to disclose

Prostate cancer (PC) kills over 300,000 men each year globally. Despite initial effectiveness, standard-of-care PC therapies targeting androgen receptor (AR) will eventually fail. AR is a potent oncogene; it cooperates with other transcription factors like FOXA1 to co-regulate genes and oncogenic activity in PC. Unfortunately, resistance to AR-signaling inhibition (ARSI) commonly emerges via selective bypass of AR signaling, or via shift toward aggressive and sometimes AR-indifferent disease phenotypes, known collectively as aggressive variant prostate cancer (AVPC). Consequently, PC patients are in desperate need of solutions to either restore effectiveness of existing drugs, or to target new pathways entirely. The AR cofactor FOXA1 has recently been shown to be essential throughout all stages of ARSI resistance and progression to AVPC, including cases where AR-dependency is lost. However, the exact behavior and binding partner(s) of FOXA1 aside from AR and other nuclear hormone receptors is largely understudied. Alongside FOXA1, the transcription factor SOX2 is upregulated in response to ARSI, directly imparts ARSI resistance, and remains highly expressed in AVPC. As such, a growing body of evidence implicates SOX2 as an emerging oncogene and protein of interest. SOX2 is an obligate heterodimer, meaning it requires another protein partner to function. However, the traditional SOX2 partner(s) OCT3/4 are not expressed in PC, and the mechanism by which SOX2 promotes therapy resistance in PC remains largely uncharacterized. We hypothesize that SOX2 engages in direct physical interaction with FOXA1 in castration-resistant/aggressive variant prostate cancers to compensate for antagonized AR-signaling during ARSI and establish a unique DNA binding profile that results in a more aggressive, therapy-resistant PC phenotype. We find, to our knowledge, the first direct evidence of a SOX2 and FOXA1 interaction in PC. SOX2 and FOXA1 physically associate and share ~80% and ~90% cistrome overlap in both AR-driven and AVPC cell lines. Functional analyses of these chromatin binding sites demonstrate SOX2 and FOXA1 co-regulated transcriptional programs associated with cell cycle progression and lineage plasticity. These findings suggest a compensatory transcriptional network in advanced PC governed by SOX2-FOXA1 cooperation, and the resulting downstream networks provide potential therapeutic opportunities beyond traditional ARSI. Our findings forge an important mechanistic understanding of how PC leverages alternative transcription factor function to evade once-effective AR-targeted therapies.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*