Resistance to BET Inhibitor Leads to Alternative Therapeutic Vulnerabilities in Castration-Resistant Prostate Cancer

Pawar, Aishwarya; Gollavilli, Paradesi Naidu; Wang, Shaomeng; Asangani, Irfan A.

doi:10.1016/j.celrep.2019.10.037

Cited by 12 publications

(14 citation statements)

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“…Our previous reports indicated that CDK9 can stimulate S81 phosphorylation of AR in the presence of androgen, whereas pS81 expression was more dependent on CDK1 under androgen ablation [17]. Consistent with our findings, a recent study demonstrated that AR re-activation can be achieved by CDK9-mediated phosphorylation and that PCa can be co-targeted by CDK9 inhibitor and AR antagonist [19]. Indeed, we determined by ChIP-qPCR that the robust occupancy of pS81 (but not total AR) at the KLK3 promoter was correlated with the recruitment of pTEFb (CDK9/Cyclin) complex and transcriptional active RNA Pol II, as marked by pS2 and pS5 (Fig.…”

Section: Ps81 Expression On the Chromatin Is Coupled To Ar-dependent Transactivation And Is Co-sustained By Cdk1 And Cdk9supporting

confidence: 92%

Phosphorylation of the androgen receptor at Ser81 is co‐sustained by CDK1 and CDK9 and leads to AR‐mediated transactivation in prostate cancer

et al. 2021

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Androgen receptor (AR) is the principal molecule in prostate cancer (PCa) etiology and therapy. AR re‐activation still remains a major challenge during treatment of castration‐resistant prostate cancer (CRPC) tumors that relapse after castration therapies. Recent reports have indicated the enrichment of Ser81‐phosphorylated AR (pS81) in the nucleus of CRPC cells, and CDK1 and CDK9 as the kinases phosphorylating AR at S81. In the current study we showed that pS81 is preferentially localized in the nucleus in both rapid biopsy metastatic CRPC samples and PCa xenografts, and nuclear pS81 localization is correlated with AR transactivation in tumor xenografts. Chromatin immunoprecipitation (ChIP) analysis demonstrated an alignment of S81 phosphorylation and AR‐mediated transactivation with the chromatin locus openness. Moreover, pS81‐specific ChIP‐Seq showed a disproportional occupancy of pS81 on AR‐activated promoters, while 3C‐ChIP assays further indicated an enrichment of pS81 at the PSA enhancer‐promoter loop, a known AR activating hub. In the latter, CDK9 was shown to modulate the transactivation of the AR and RNA Pol II. Indeed, ChIP and re‐ChIP assays also confirmed that AR‐dependent activation of the PSA enhancer and promoter mediated by pS81 was coupled with activation of Pol II and the pTEFb complex. Mechanistically, we determined that CDK1 and CDK9 sustained the pS81 AR modification in the soluble and chromatin‐bound fractions of PCa cells, respectively. Finally, we demonstrated that CDK1 activity was maintained throughout the cell cycle, and that CDK1 inhibitors restored androgen sensitivity in CRPC tumor cells. Based on these findings, CDK1 and CDK9 could be targeted as pS81 kinases in patients with CRPC, either alone or in conjunction with direct AR antagonists.

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Section: Ps81 Expression On the Chromatin Is Coupled To Ar-dependent Transactivation And Is Co-sustained By Cdk1 And Cdk9supporting

confidence: 92%

Phosphorylation of the androgen receptor at Ser81 is co‐sustained by CDK1 and CDK9 and leads to AR‐mediated transactivation in prostate cancer

et al. 2021

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“…Mechanistically, BET inhibitors downregulate various proteins involved in homologous recombination, including BRCA1, BRCA2, RAD51 and RBBP8 (also known as CtIP), suggesting broad effects on the expression DDR-related genes rather than a targeted synthetic lethality (as epitomized by PARP inhibition in cancers associated with germline BRCA mutations). Interestingly, a reciprocal observation was made in models of BET inhibitor-resistant CRPC, whereby acquired polycomb repressive complex 2 (PRC2)-mediated silencing of DDR-related genes led to increased sensitivity to PARP inhibitors 114 . Combinations of PARP and BET inhibitors have not yet been evaluated in clinical studies.…”

Section: Parp Inhibitorsmentioning

confidence: 99%

Combining epigenetic drugs with other therapies for solid tumours — past lessons and future promise

Morel

Jeffery

Aspeslagh³

et al. 2019

Nat Rev Clin Oncol

321

271

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HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

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“…In triple-negative breast cancer (TNBC), gatekeeper mutations, new driver gene alterations, and drug pump activation were not observed in BET-resistant TNBC cells [28]. This was true in other malignant tumors such as ovarian cancer, prostate cancer, and leukemia, in which alternative signaling pathways other than BET itself were associated with acquired resistance [50][51][52][53]. Therefore, it is possible that NMC might not acquire gatekeeper mutations, although we did not evaluate the mutations in bromodomains in resistant NMC cells.…”

Section: Discussionmentioning

confidence: 99%

SETD2 and miR-21 as therapeutic targets for NUT midline carcinoma

Yoshida¹,

Okumura²,

Sasaki³

et al. 2021

Preprint

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Background:Nuclear protein in testis (NUT) midline carcinoma (NMC) is a rare and highly aggressive tumor with the bromodomain containing 4 (BRD4)-NUT (NUTM1) gene fusion. BRD4 is a member of the bromodomain and extra-terminal domain (BET) family of proteins, and BET inhibitors have been investigated in NMC clinical trials. However, few targeted therapies are available for NMC, and novel therapeutic targets remain to be determined. We determined the role of two epigenetic regulators as possible therapeutic targets for NMC. Methods:We performed next-generation sequencing (NGS) in NMC cell lines (HCC2429 and Ty82). H3K36me3 expression was studied using western blotting. The efficacy of AZD1775, a WEE1 inhibitor, was evaluated using the MTS and γH2AX assays. We established an NMC cell line that was resistant to BET inhibitors. The sensitivity of the cells resistant to AZD1775 was analyzed using the MTS assay. RNA sequencing was performed to determine miRNA expression levels. TaqMan miRNA assays were used to analyze miR-21 expression. The efficacy of the miR-21 inhibitor was evaluated using the MTS assay. We established a digital PCR (dPCR) assay to detect NUT gene rearrangements to identify patients with NMC. Using NGS, a patient with NMC was identified with the SETD2 mutation.Results:SETD2 mutation (p.Ser2382fs) was determined in NMC cells, in which H3K36me3 expression was depleted, indicating SETD2 loss. NMC cells were sensitive to the WEE1 inhibitor, AZD1775 in cancer cells with SETD2 deficiency. γH2AX expression was increased in NMC cells treated with AZD1775. The efficacy of the combination of AZD1775 and JQ-1 was additive. We established NMC cells that were resistant to BET inhibitors. The resistant cells were also sensitive to AZD1775. miRNA analysis revealed increased miR-21 expression in BET-inhibitor-resistant NMC cells. MiR-21 regulated the growth of NMCs. The miR-21 inhibitor suppressed the growth of BET-inhibitor-resistant cells. Thirty-two clinical samples were analyzed and NMC was identified using digital PCR assays. Tumors with the SETD2 mutation were analyzed using NGS.Conclusions:We report for the first time SET domain-containing protein 2 (SETD2) deficiency and miR-21 as novel therapeutic targets for NMC. SETD2 loss and miR-21 may be therapeutic targets for NMC.Trial registrationIn this study, we analyzed the gene alterations in human tumor samples. This study was registered in the UMIN clinical trial registered system (UMIN000043147, January 27, 2021).

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Resistance to BET Inhibitor Leads to Alternative Therapeutic Vulnerabilities in Castration-Resistant Prostate Cancer

Cited by 12 publications

References 0 publications

Phosphorylation of the androgen receptor at Ser81 is co‐sustained by CDK1 and CDK9 and leads to AR‐mediated transactivation in prostate cancer

Phosphorylation of the androgen receptor at Ser81 is co‐sustained by CDK1 and CDK9 and leads to AR‐mediated transactivation in prostate cancer

Combining epigenetic drugs with other therapies for solid tumours — past lessons and future promise

SETD2 and miR-21 as therapeutic targets for NUT midline carcinoma

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