RT Journal Article
SR Electronic
T1 Aberrant Expression of ERG Promotes Resistance to Combined PI3K and AR Pathway Inhibition through Maintenance of AR Target Genes
JF Molecular Cancer Therapeutics
JO Mol Cancer Ther
FD American Association for Cancer Research
SP 1577
OP 1586
DO 10.1158/1535-7163.MCT-18-1386
VO 18
IS 9
A1 Mao, Ninghui
A1 Gao, Dong
A1 Hu, Wenhuo
A1 Hieronymus, Haley
A1 Wang, Shangqian
A1 Lee, Young Sun
A1 Lee, Cindy
A1 Choi, Danielle
A1 Gopalan, Anuradha
A1 Chen, Yu
A1 Carver, Brett S.
YR 2019
UL http://mct.aacrjournals.org/content/18/9/1577.abstract
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.