Androgen Receptor Variants Mediate DNA Repair after Prostate Cancer Irradiation

Yin, Yi; Li, Rui; Xu, Kangling; Ding, Sentai; Li, Jeffrey; Baek, Guem Hee; Ramanand, Susmita G.; Ding, Sam; Liu, Zhao; Gao, Yunpeng; Kanchwala, Mohammed; Li, Xiangyi; Hutchinson, Ryan; Liu, Xihui; Woldu, Solomon L.; Xing, Chao; Desai, Neil B.; Feng, Felix Y.; Burma, Sandeep; Bono, Johann S. de; Dehm, Scott M.; Mani, Ram S.; Chen, Benjamin P.C.; Raj, Ganesh V.

doi:10.1158/0008-5472.can-17-0164

Cited by 61 publications

(71 citation statements)

References 20 publications

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“…In addition, pre-treatment with ENZ led to more profound DNA damage (phospho-γH2A.X foci) compared to RLT alone. This is in line with in vitro studies reporting that treatment with ENZ combined with irradiation [ 15 , 16 ] or the p oly ( A DP- R ibose) p olymerase inhibitor olaparib [ 17 ] increased the number of phospho-γH2A.X foci resulting from either treatment (X-ray or olaparib) alone.…”

Section: Discussionsupporting

confidence: 87%

Preclinical evaluation of PSMA expression in response to androgen receptor blockade for theranostics in prostate cancer

et al. 2018

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BackgroundProstate-specific membrane antigen (PSMA)-directed radioligand therapy (RLT) is a promising yet not curative approach in castration-resistant (CR) prostate cancer (PC). Rational combination therapies may improve treatment efficacy. Here, we explored the effect of androgen receptor blockade (ARB) on PSMA expression visualized by PET and its potential additive effect when combined with 177Lu-PSMA RLT in a mouse model of prostate cancer.MethodsMice bearing human CRPC (C4-2 cells) xenografts were treated with 10 mg/kg enzalutamide (ENZ), with 50 mg/kg bicalutamide (BIC), or vehicle (control) for 21 days. PSMA expression was evaluated by 68Ga-PSMA11 PET/CT and quantified by flow cytometry of tumor fine needle aspirations before treatment and on days 23, 29, 34, and 39 post-therapy induction. For the RLT combination approach, mice bearing C4-2 tumors were treated with 10 mg/kg ENZ or vehicle for 21 days before receiving either 15 MBq (84 GBq/μmol) 177Lu-PSMA617 or vehicle. DNA damage was assessed as phospho-γH2A.X foci in tumor biopsies. Reduction of tumor volume on CT and survival were used as study endpoints.ResultsTumor growth was delayed by ARB while 68Ga-PSMA11 uptake increased up to 2.3-fold over time when compared to controls. ABR-induced upregulation of PSMA expression was confirmed by flow cytometry. Phospho-γH2A.X levels increased 1.8- and 3.4-fold at 48 h in response to single treatment ENZ or RLT and ENZ+RLT, respectively. Despite significantly greater DNA damage and persistent increase of PSMA expression at the time of RLT, no additional tumor growth retardation was observed in the ENZ+RLT group (vs. RLT only, p = 0.372 at day 81). Median survival did not improve significantly when ENZ was combined with RLT.ConclusionARB-mediated increases in PSMA expression in PC xenografts were evident by 68Ga-PSMA11 PET imaging and flow cytometry. 177Lu-PSMA617 effectively decreased C4-2 tumor size. However, while pre-treatment with ARB increased DNA damage significantly, it did not result in synergistic effects when combined with RLT.Electronic supplementary materialThe online version of this article (10.1186/s13550-018-0451-z) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 87%

Preclinical evaluation of PSMA expression in response to androgen receptor blockade for theranostics in prostate cancer

et al. 2018

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“…Our data suggest that retention of DNA-PKcs on chromatin in AR-overexpressing cells hinders completing the DNA repair process confirmed by an impaired DNA end-ligation assay, contributing to the elevated and persistent DNA damage induced by SPA. Notably, a previous study determined that AR splice variants (ARVs) could promote the repair of DNA damage induced by radiation via binding of ARVs to the catalytic subunit of DNA-PK (62). In contrast to ADT, which increases the expression of ARVs, SPA has been shown to repress the expression of ARVs (10), a result expected to compromise ARV-mediated DNA repair and promote growth arrest.…”

Section: Methodsmentioning

confidence: 99%

Supraphysiological androgens suppress prostate cancer growth through androgen receptor–mediated DNA damage

Chatterjee¹,

Schweizer²,

Lucas³

et al. 2019

Journal of Clinical Investigation

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Prostate cancer (PC) initially depends on androgen receptor (AR) signaling for survival and growth. Therapeutics designed to suppress AR activity serve as the primary intervention for advanced disease. However, supraphysiological androgen (SPA) concentrations can produce paradoxical responses leading to PC growth inhibition. We sought to discern the mechanisms by which SPA inhibits PC and to determine if molecular context associates with antitumor activity. SPA produced an ARmediated, dose-dependent induction of DNA double-strand breaks, G 0 /G 1 cell-cycle arrest, and cellular senescence. SPA repressed genes involved in DNA repair and delayed the restoration of damaged DNA, which was augmented by poly (ADPribose) polymerase 1 inhibition. SPA-induced double-strand breaks were accentuated in BRCA2-deficient patients with PC, and combining SPA with poly (ADP-ribose) polymerase or DNA-dependent protein kinase inhibition further repressed growth. Next-generation sequencing was performed on biospecimens from patients with PC receiving SPA as part of ongoing phase II clinical trials. Patients with mutations in genes mediating homology-directed DNA repair were more likely to exhibit clinical responses to SPA. These results provide a mechanistic rationale for directing SPA therapy to patients with PC who have AR amplification or DNA repair deficiency and for combining SPA therapy with poly (ADP-ribose) polymerase inhibition.

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“…One mechanism proposed to underlie poor responses to radiotherapy combined with ADT or AR-LBD inhibitors is the expression of AR-Vs. Prostate cancer cells that express AR-Vs either alone or together with full-length AR do not exhibit synergism between ADT and radiotherapy that is observed in cells that express solely full-length AR [ 27 ]. The clinical regimen of 2–3 months of neoadjuvant ADT prior to radiotherapy increases the expression of AR-Vs in prostate cancer patients [ 27 ]. These clinical data are consistent with other reports showing that ADT increases the expression of AR-Vs in prostate tissue [ 28 , 29 , 30 ].…”

Section: Introductionmentioning

confidence: 99%

Ralaniten Sensitizes Enzalutamide-Resistant Prostate Cancer to Ionizing Radiation in Prostate Cancer Cells that Express Androgen Receptor Splice Variants

Bañuelos¹,

Ito²,

Obst³

et al. 2020

Cancers

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Blocking androgen receptor (AR) transcriptional activity by androgen deprivation therapy (ADT) improves the response to radiotherapy for intermediate and high risk prostate cancer. Unfortunately, ADT, antiandrogens, and abiraterone increase expression of constitutively active splice variants of AR (AR-Vs) which regulate DNA damage repair leading to resistance to radiotherapy. Here we investigate whether blocking the transcriptional activities of full-length AR and AR-Vs with ralaniten leads to enhanced sensitivity to radiotherapy. Combination therapies using ralaniten with ionizing radiation were evaluated for effects on proliferation, colony formation, cell cycle, DNA damage, and Western blot analyses in human prostate cancer cells that express both full-length AR and AR-Vs. Ralaniten and a potent next-generation analog (EPI-7170) decreased expression of DNA repair genes whereas enzalutamide had no effect. FACS analysis revealed a dose-dependent decrease of BrdU incorporation with increased accumulation of γH2AX with a combination of ionizing radiation with ralaniten. An additive inhibitory effect on proliferation of enzalutamide-resistant cells was achieved with a combination of ralaniten compounds with ionizing radiation. Ralaniten and EPI-7170 sensitized prostate cancer cells that express full-length AR and AR-Vs to radiotherapy whereas enzalutamide had no added benefit.

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Androgen Receptor Variants Mediate DNA Repair after Prostate Cancer Irradiation

Cited by 61 publications

References 20 publications

Preclinical evaluation of PSMA expression in response to androgen receptor blockade for theranostics in prostate cancer

Preclinical evaluation of PSMA expression in response to androgen receptor blockade for theranostics in prostate cancer

Supraphysiological androgens suppress prostate cancer growth through androgen receptor–mediated DNA damage

Ralaniten Sensitizes Enzalutamide-Resistant Prostate Cancer to Ionizing Radiation in Prostate Cancer Cells that Express Androgen Receptor Splice Variants

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