Role of androgen receptor splice variant-7 (AR-V7) in prostate cancer resistance to 2nd-generation androgen receptor signaling inhibitors

Yezi Zhu, Susan L. Dalrymple, Ilsa Coleman, S. Lilly Zheng, Jianfeng Xu, Jody E. Hooper, Emmanuel S. Antonarakis, Angelo M. De Marzo, Alan K. Meeker, Peter S. Nelson, William B. Isaacs, Samuel R. Denmeade, Jun Luo, W. Nathaniel Brennen, John T. Isaacs

Research output: Contribution to journalArticlepeer-review

Abstract

The role of truncated androgen receptor splice variant-7 (AR-V7) in prostate cancer biology is an unresolved question. Is it simply a marker of resistance to 2nd-generation androgen receptor signaling inhibitors (ARSi) like abiraterone acetate (Abi) and enzalutamide (Enza) or a functional driver of lethal resistance via its ligand-independent transcriptional activity? To resolve this question, the correlation between resistance to ARSi and genetic chances and expression of full length AR (AR-FL) vs. AR-V7 were evaluated in a series of independent patient-derived xenografts (PDXs). While all PDXs lack PTEN expression, there is no consistent requirement for mutation in TP53, RB1, BRCA2, PIK3CA, or MSH2, or expression of SOX2 or ERG and ARSi resistance. Elevated expression of AR-FL alone is sufficient for Abi but not Enza resistance, even if AR-FL is gain-of-function (GOF) mutated. Enza resistance is consistently correlated with enhanced AR-V7 expression. In vitro and in vivo growth responses of Abi-/Enza-resistant LNCaP-95 cells in which CRISPR-Cas9 was used to knockout AR-FL or AR-V7 alone or in combination were evaluated. Combining these growth responses with RNAseq analysis demonstrates that both AR-FL- and AR-V7-dependent transcriptional complementation are needed for Abi/Enza resistance.

Original languageEnglish (US)
Pages (from-to)6935-6949
Number of pages15
JournalOncogene
Volume39
Issue number45
DOIs
StatePublished - Nov 5 2020
Externally publishedYes

Bibliographical note

Funding Information:
Acknowledgements We are grateful to the patients and their families who participated in the Legacy Gift Rapid Autopsy program at Hopkins. We would like to acknowledge the Department of Defense Prostate Cancer Research Program W81XWH1810349 (JTI), W81XWH-17-1-0528 (WNB), W81XWH-18-2-0015 (AMM) and NIH Prostate SPOREs P50 CA058236 (JTI), Pathology Core from the Prostate SPORE P50 CA058236 (AMM) and P50 CA097186 (PSN), W81XWH-18-1-0347 (PSN), P01 CA163227 (PSN), Emerson Collective Cancer Research Fund [643396, (WNB)], Allegheny Health Network-Johns Hopkins University Cancer Research Fund (WNB), R01 CA185297 (JL and ESA). Also, we wish to thank the Cell Imaging Facility, Animal Core Facility, Tissue Histology Core, Genetic Resource Core, Cytogenetics Core Facility, and the Autopsy Core from the CCSG Grant supported by the SKCCC CCSG (P30 CA006973) for their services and assistance.

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

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