Aberrant expression of ERG promotes resistance to combined PI3K and AR pathway inhibition through maintenance of AR target genes Journal Article


Authors: Mao, N.; Gao, D.; Hu, W.; Hieronymus, H.; Wang, S.; Lee, Y. S.; Lee, C.; Choi, D.; Gopalan, A.; Chen, Y.; Carver, B. S.
Article Title: Aberrant expression of ERG promotes resistance to combined PI3K and AR pathway inhibition through maintenance of AR target genes
Abstract: 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. © 2019 American Association for Cancer Research.
Journal Title: Molecular Cancer Therapeutics
Volume: 18
Issue: 9
ISSN: 1535-7163
Publisher: American Association for Cancer Research  
Date Published: 2019-09-01
Start Page: 1577
End Page: 1586
Language: English
DOI: 10.1158/1535-7163.Mct-18-1386
PUBMED: 31296553
PROVIDER: scopus
PMCID: PMC6726496
DOI/URL:
Notes: Source: Scopus
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MSK Authors
  1. Yu Chen
    81 Chen
  2. Anuradha Gopalan
    332 Gopalan
  3. Brett Stewart Carver
    121 Carver
  4. Wenhuo Hu
    41 Hu
  5. Dong Gao
    24 Gao
  6. Ninghui   Mao
    10 Mao
  7. Shangqian   Wang
    16 Wang
  8. Danielle Wai-pui Li
    8 Li
  9. Young Sun Lee
    6 Lee
  10. Cindy J Lee
    1 Lee