TY - JOUR
T1 - Integrative molecular analyses define correlates of high B7-H3 expression in metastatic castrate-resistant prostate cancer
AU - Shi, Xiaolei
AU - Day, Abderrahman
AU - Bergom, Hannah E.
AU - Tape, Sydney
AU - Baca, Sylvan C.
AU - Sychev, Zoi E.
AU - Larson, Gabrianne
AU - Bozicevich, Asha
AU - Drake, Justin M.
AU - Zorko, Nicholas
AU - Wang, Jinhua
AU - Ryan, Charles J.
AU - Antonarakis, Emmanuel S.
AU - Hwang, Justin
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - B7-H3 (CD276) is an immune checkpoint overexpressed in prostate cancer with minimal expression in normal tissues and associated with poor prognosis, making it an excellent therapy target. We interrogated B7-H3 expression and its regulation in metastatic castration-resistant prostate cancer (mCRPC). We found greater expression of B7-H3 transcript relative to other immunotherapy targets (CTLA-4, PD-L1/2), including in tumors that lacked expression of prostate-specific membrane antigen (PSMA). Enzalutamide-resistant mCRPC cells demonstrated increased amounts of B7-H3, and this was associated with resistance signaling pathways. Using a machine-learning algorithm, the gene network of B7-H3 was strongly correlated with androgen receptor (AR) and AR co-factor (HOXB13, FOXA1) networks. In mCRPC samples, the B7-H3 promoter and distal enhancer regions exhibited enhanced transcriptional activity and were directly bound by AR and its co-factors. Altogether, our study characterizes molecular profiles and epigenetic regulation of B7-H3-expressing mCRPC tumors, which informs optimal precision-oncology approaches for mCRPC patients.
AB - B7-H3 (CD276) is an immune checkpoint overexpressed in prostate cancer with minimal expression in normal tissues and associated with poor prognosis, making it an excellent therapy target. We interrogated B7-H3 expression and its regulation in metastatic castration-resistant prostate cancer (mCRPC). We found greater expression of B7-H3 transcript relative to other immunotherapy targets (CTLA-4, PD-L1/2), including in tumors that lacked expression of prostate-specific membrane antigen (PSMA). Enzalutamide-resistant mCRPC cells demonstrated increased amounts of B7-H3, and this was associated with resistance signaling pathways. Using a machine-learning algorithm, the gene network of B7-H3 was strongly correlated with androgen receptor (AR) and AR co-factor (HOXB13, FOXA1) networks. In mCRPC samples, the B7-H3 promoter and distal enhancer regions exhibited enhanced transcriptional activity and were directly bound by AR and its co-factors. Altogether, our study characterizes molecular profiles and epigenetic regulation of B7-H3-expressing mCRPC tumors, which informs optimal precision-oncology approaches for mCRPC patients.
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U2 - 10.1038/s41698-022-00323-2
DO - 10.1038/s41698-022-00323-2
M3 - Article
C2 - 36323882
AN - SCOPUS:85141129605
SN - 2397-768X
VL - 6
JO - npj Precision Oncology
JF - npj Precision Oncology
IS - 1
M1 - 80
ER -