Ablation of the oncogenic transcription factor ERG by deubiquitinase inhibition in prostate cancer

Wang, Shan; Kollipara, Rahul K.; Srivastava, N. K.; Li, Rui; Ravindranathan, Preethi; Hernández, Elizabeth; Freeman, Eva; Humphries, Caroline G.; Kapur, Payal; Lotan, Yair; Fazli, Ladan; Gleave, Martin; Plymate, Stephen R.; Raj, Ganesh V.; Hsieh, Jer Tsong; Kittler, Ralf

doi:10.1073/pnas.1322198111

Cited by 112 publications

(118 citation statements)

References 28 publications

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“…4 As was recently demonstrated, the WP1130 chemotype may be useful against various cancers with overexpressed or activated Usp9x. 12 Mcl-1 was previously reported to be a substrate of Usp9x in some tumors. 5 We sought to confirm a direct role for Usp9x as an Mcl-1 regulator by assessing the response to Usp9x KD and identified several unexpected outcomes.…”

Section: Discussionmentioning

confidence: 98%

“…by guest www.bloodjournal.org From Small-molecule-mediated Usp9x/Usp24 inhibition WP1130 was the first small molecule described with Usp9x inhibitory activity and has shown activity against specific tumors in vitro and in vivo. 9,12,20 However, other DUBs are also WP1130 targets, with some recognized benefits and risks associated with the use of a partially selective DUB inhibitor in a clinical setting. 4 The main limitation for WP1130 as a clinical candidate is its low aqueous solubility (;2.3 mM), which limits its delivery and bioavailability.…”

Section: Usp9x and Usp24 Interact With Mcl-1mentioning

confidence: 99%

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Targeting deubiquitinase activity with a novel small-molecule inhibitor as therapy for B-cell malignancies

Peterson

Sun

Liu

et al. 2015

Blood

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Section: Discussionmentioning

confidence: 98%

Section: Usp9x and Usp24 Interact With Mcl-1mentioning

confidence: 99%

Targeting deubiquitinase activity with a novel small-molecule inhibitor as therapy for B-cell malignancies

Peterson

Sun

Liu

et al. 2015

Blood

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“…USP9X is a deubquitinating enzyme that has been suggested to have a protumorigenic role by preventing the ubiquitinmediated degradation of prosurvival and growth proteins, such as MCL2 and ERG (37)(38)(39)(40). Furthermore, increased expression of USP9X was proposed to mediate resistance to glucocorticoids in ALL (40).…”

Section: Temporal Association Of Somatic Mutations Between Diagnosis Andmentioning

confidence: 99%

Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome

Schwartzman

Savino

Gombert

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Children with Down syndrome (DS) are prone to development of high-risk B-cell precursor ALL (DS-ALL), which differs genetically from most sporadic pediatric ALLs. Increased expression of cytokine receptor-like factor 2 (CRLF2), the receptor to thymic stromal lymphopoietin (TSLP), characterizes about half of DS-ALLs and also a subgroup of sporadic "Philadelphia-like" ALLs. To understand the pathogenesis of relapsed DS-ALL, we performed integrative genomic analysis of 25 matched diagnosis-remission and -relapse DSALLs. We found that the CRLF2 rearrangements are early events during DS-ALL evolution and generally stable between diagnoses and relapse. Secondary activating signaling events in the JAK-STAT/ RAS pathway were ubiquitous but highly redundant between diagnosis and relapse, suggesting that signaling is essential but that no specific mutations are "relapse driving." We further found that activated JAK2 may be naturally suppressed in 25% of CRLF2 pos DSALLs by loss-of-function aberrations in USP9X, a deubiquitinase previously shown to stabilize the activated phosphorylated JAK2. Interrogation of large ALL genomic databases extended our findings up to 25% of CRLF2 pos , Philadelphia-like ALLs. Pharmacological or genetic inhibition of USP9X, as well as treatment with low-dose ruxolitinib, enhanced the survival of pre-B ALL cells overexpressing mutated JAK2. Thus, somehow counterintuitive, we found that suppression of JAK-STAT "hypersignaling" may be beneficial to leukemic B-cell precursors. This finding and the reduction of JAK mutated clones at relapse suggest that the therapeutic effect of JAK specific inhibitors may be limited. Rather, combined signaling inhibitors or direct targeting of the TSLP receptor may be a useful therapeutic strategy for DS-ALL.C hildren with Down syndrome (DS) are at a markedly increased risk for B-cell precursor acute lymphoblastic leukemia (BCP-ALL) (1). The poor survival of DS-ALL compared with ALL in children without DS ("sporadic" ALL) is related to increased treatment toxicity and to increased incidence of relapse (2). Thus, better therapy is needed for these patients.Previous studies by our group and others revealed differences between the genetics of DS-ALLs and of sporadic ALLs (3-6). The typical cytogenetic subgroups, ETV6-RUNX1 and hyperdiploid ALLs, are less common in DS-ALLs. Acquired somatic activation of the thymic stromal lymphopoietin (TSLP) pathway are present at diagnosis in about half of DS-ALLs. Aberrant expression of cytokine receptor-like factor 2 (CRLF2) in these leukemias is caused by chromosomal rearrangements consisting either of a microdeletion on chromosome X, juxtaposing the promoter of P2RY8 with the coding region of CRLF2, or by a translocation of CRLF2 into the Ig heavy chain (IgH) locus. CRLF2 heterodimerizes with IL7 receptor-α (IL7R) to form the receptor to TSLP (reviewed in ref. 7). TSLP receptors signal by activation of the JAK-STAT pathway. Interestingly, in the majority of DS-ALLs, SignificanceChildren with Down syndrome are at increased risk ...

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“…In several studies done in the recent past, USP9X inhibition by WP1130 promotes apoptosis by reducing MCL-1 levels and increased tumor cell sensitivity to chemotherapy (39). Recently, USP9X inhibition by WP1130 was shown to inhibit the growth of ERG-positive tumors in vitro and in mouse xenograft models of prostate cancer (40). Our laboratory has been actively engaged in identifying derivatives with greater selectivity, activity, and drug-like properties.…”

Section: Usp9x Inhibitors: Wp1130 and Its Derivativesmentioning

confidence: 99%

Emerging Potential of Therapeutic Targeting of Ubiquitin-Specific Proteases in the Treatment of Cancer

2014

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The ubiquitin-proteasome system (UPS) has emerged as a therapeutic focus and target for the treatment of cancer. The most clinically successful UPS-active agents (bortezomib and lenalidomide) are limited in application to hematologic malignancies, with only marginal efficacy in solid tumors. Inhibition of specific ubiquitin E3 ligases has also emerged as a valid therapeutic strategy, and many targets are currently being investigated. Another emerging and promising approach in regulation of the UPS involves targeting deubiquitinases (DUB). The DUBs comprise a relatively small group of proteins, most with cysteine protease activity that target several key proteins involved in regulation of tumorigenesis, apoptosis, senescence, and autophagy. Through their multiple contacts with ubiquitinated protein substrates involved in these pathways, DUBs provide an untapped means of modulating many important regulatory proteins that support oncogenic transformation and progression. Ubiquitin-specific proteases (USP) are one class of DUBs that have drawn special attention as cancer targets, as many are differentially expressed or activated in tumors or their microenvironment, making them ideal candidates for drug development. This review attempts to summarize the USPs implicated in different cancers, the current status of USP inhibitor-mediated pharmacologic intervention, and future prospects for USP inhibitors to treat diverse cancers. Cancer Res; 74(18); 4955-66. Ó2014 AACR.

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Ablation of the oncogenic transcription factor ERG by deubiquitinase inhibition in prostate cancer

Cited by 112 publications

References 28 publications

Targeting deubiquitinase activity with a novel small-molecule inhibitor as therapy for B-cell malignancies

Targeting deubiquitinase activity with a novel small-molecule inhibitor as therapy for B-cell malignancies

Suppressors and activators of JAK-STAT signaling at diagnosis and relapse of acute lymphoblastic leukemia in Down syndrome

Emerging Potential of Therapeutic Targeting of Ubiquitin-Specific Proteases in the Treatment of Cancer

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