PT  - JOURNAL ARTICLE
AU  - Mao, Ninghui
AU  - Gao, Dong
AU  - Hu, Wenhuo
AU  - Hieronymus, Haley
AU  - Wang, Shangqian
AU  - Lee, Young Sun
AU  - Lee, Cindy
AU  - Choi, Danielle
AU  - Gopalan, Anuradha
AU  - Chen, Yu
AU  - Carver, Brett S.
TI  - Aberrant Expression of ERG Promotes Resistance to Combined PI3K and AR Pathway Inhibition through Maintenance of AR Target Genes
AID  - 10.1158/1535-7163.MCT-18-1386
DP  - 2019 Sep 01
TA  - Molecular Cancer Therapeutics
PG  - 1577--1586
VI  - 18
IP  - 9
4099  - http://mct.aacrjournals.org/content/18/9/1577.short
4100  - http://mct.aacrjournals.org/content/18/9/1577.full
SO  - Mol Cancer Ther2019 Sep 01; 18
AB  - On the basis of our previous work defining the molecular rationale for combined targeting of the PI3K and AR pathways in PTEN loss prostate cancer, the first clinical trial was recently reported demonstrating a significant benefit for combination therapy in patients with metastatic prostate cancer. In this phase II trial, loss of PTEN was a biomarker predictive of response to combined AKT and AR inhibition. Given that PTEN loss prostate cancers are significantly enriched for ERG genomic rearrangements, we evaluated how the aberrant expression of ERG may impact response to PI3K/AR-targeted therapy. Here, we show that overexpression of ERG in the setting of Pten loss promotes resistance to combined PI3K and AR pathway inhibition with associated maintenance of AR target gene expression. Importantly, following AR knockout in the setting of ERG overexpression, there is maintenance of a subset of AR lineage–specific target genes, making AR dispensable in this context. This has important clinical implications as even in the setting of the androgen-regulated TMPRSS2:ERG genomic rearrangement, ERG expression is never abolished following AR inhibition and may allow for cell survival following AR (lineage)–targeted therapies.