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Despite the development of second-generation antiandrogens, acquired resistance to hormone therapy remains a major challenge in treating advanced prostate cancer. We find that cancer-associated fibroblasts (CAFs) can promote antiandrogen resistance in mouse models and in prostate organoid cultures. We identify neuregulin 1 (NRG1) in CAF supernatant, which promotes resistance in tumor cells through activation of HER3. Pharmacological blockade of the NRG1/HER3 axis using clinical-grade blocking antibodies re-sensitizes tumors to hormone deprivation in vitro and in vivo. Furthermore, patients with castration-resistant prostate cancer with increased tumor NRG1 activity have an inferior response to second-generation antiandrogen therapy. This work reveals a paracrine mechanism of antiandrogen resistance in prostate cancer amenable to clinical testing using available targeted therapies., Competing Interests: Declaration of Interests C.L.S. and J.W. are co-inventors of enzalutamide and apalutamide and may be entitled to royalties. C.L.S. serves on the Board of Directors of Novartis and is a co-founder of ORIC Pharmaceuticals. He is a science advisor to Agios, Beigene, Blueprint, Column Group, Foghorn, Housey Pharma, Nextech, KSQ, Petra, and PMV. W.A. reports consulting for Clovis Oncology, Janssen, MORE Health, and ORIC Pharmaceuticals, and received honoraria from CARET and travel accommodations from GlaxoSmith Kline, Clovis Oncology, and ORIC Pharmaceuticals. D.E.R. reports having consulting or advisory role (uncompensated) from Genentech/Roche, Janssen Oncology, and TRACON Pharma, and received research funding from: AstraZeneca (Inst); Celgene (Inst); Ferring (Inst); Genentech/Roche (Inst); Janssen Oncology (Inst); Medivation/Astellas/Pfizer (Inst); Millennium (Inst); Novartis (Inst); Taiho Pharmaceutical (Inst); Takeda (Inst); TRACON Pharma (Inst). W.R.K. is a coinventor on patent WO2012168930A2 filed by Koninklijke Nederlandse Akademie Van Wetenschappen that covers organoid technology., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

In prostate cancer, resistance to the antiandrogen enzalutamide (Enz) can occur through bypass of androgen receptor (AR) blockade by the glucocorticoid receptor (GR). In contrast to fixed genomic alterations, here we show that GR-mediated antiandrogen resistance is adaptive and reversible due to regulation of GR expression by a tissue-specific enhancer. GR expression is silenced in prostate cancer by a combination of AR binding and EZH2-mediated repression at the GR locus, but is restored in advanced prostate cancers upon reversion of both repressive signals. Remarkably, BET bromodomain inhibition resensitizes drug-resistant tumors to Enz by selectively impairing the GR signaling axis via this enhancer. In addition to revealing an underlying molecular mechanism of GR-driven drug resistance, these data suggest that inhibitors of broadly active chromatin-readers could have utility in nuanced clinical contexts of acquired drug resistance with a more favorable therapeutic index.

Some cancers evade targeted therapies through a mechanism known as lineage plasticity, whereby tumor cells acquire phenotypic characteristics of a cell lineage whose survival no longer depends on the drug target. We use in vitro and in vivo human prostate cancer models to show that these tumors can develop resistance to the antiandrogen drug enzalutamide by a phenotypic shift from androgen receptor (AR)-dependent luminal epithelial cells to AR-independent basal-like cells. This lineage plasticity is enabled by the loss of TP53 and RB1 function, is mediated by increased expression of the reprogramming transcription factor SOX2, and can be reversed by restoring TP53 and RB1 function or by inhibiting SOX2 expression. Thus, mutations in tumor suppressor genes can create a state of increased cellular plasticity that, when challenged with antiandrogen therapy, promotes resistance through lineage switching., (Copyright © 2017, American Association for the Advancement of Science.)