Bromodomain 4 inhibition leads to MYCN downregulation in Wilms tumor

Abstract

Background: Wilms tumor is the most common childhood kidney cancer. Two distinct histological subtypes of Wilms tumor have been described: tumors lacking anaplasia (the favorable subtype) and tumors displaying anaplastic features (the unfavorable subtype). Children with favorable disease generally have a very good prognosis, whereas those with anaplasia are oftentimes refractory to standard treatments and suffer poor outcomes, leading to an unmet clinical need. MYCN dysregulation has been associated with a number of pediatric cancers including Wilms tumor. Procedures:In this context, we undertook a functional genomics approach to uncover novel therapeutic strategies for those patients with anaplastic Wilms tumor. Genomic analysis and in vitro experimentation demonstrate that cell growth can be reduced by modulating MYCN overexpression via bromodomain 4 (BRD4) inhibition in both anaplastic and nonanaplastic Wilms tumor models. Results: We observed a time-dependent reduction of MYCN and MYCC protein levels upon BRD4 inhibition in Wilms tumor cell lines, which led to cell death and proliferation suppression. BRD4 inhibition significantly reduced tumor volumes in Wilms tumor patient-derived xenograft (PDX) mouse models. Conclusions: We suggest that AZD5153, a novel dual-BRD4 inhibitor, can reduce MYCN levels in both anaplastic and nonanaplastic Wilms tumor cell lines, reduces Abbreviations: AUC, area under the curve; BRD4, bromodomain 4; OS, overall survival; PDX, patient-derived xenograft

Advances in the clinical management of high‐risk Wilms tumors

“…DS‐8201a, a HER2 antibody conjugated to a topoisomerase 1 payload, and Selinexor, 48–50 an inhibitor of the nuclear pore XPO1, are two agents with promising laboratory data, which are undergoing clinical trials in other pediatric solid tumors and thus may be amenable to clinical investigations in WT. The heterogeneous genomic landscape of WT makes it challenging to identify selective inhibitors that are effective across all high‐risk WT cases; however, therapeutic vulnerabilities have been identified that could benefit particular subsets of patients; for example, CDK9 inhibitors in MLL1/ENL mutant tumors, 51 BRD4 inhibitors in MYCN‐driven tumors, 52 as well as WT with specific DNA damage response defects such as deleterious mutations in ATM via the ATR inhibitor elimusertib on NCT05071209 (PEPN2112).…”

“…The heterogeneous genomic landscape of WT makes it challenging to identify selective inhibitors that are effective across all high-risk WT cases; however, therapeutic vulnerabilities have been identified that could benefit particular subsets of patients; for example, CDK9 inhibitors in MLL1/ENL mutant tumors, 51 BRD4 inhibitors in MYCNdriven tumors, 52 as well as WT with specific DNA damage response defects such as deleterious mutations in ATM via the ATR inhibitor elimusertib on NCT05071209 (PEPN2112).…”

AZD5153, a Bivalent BRD4 Inhibitor, Suppresses Hepatocarcinogenesis by Altering BRD4 Chromosomal Landscape and Modulating the Transcriptome of HCC Cells

“…AZD5153 exhibited improved potency compared to single bromodomain inhibitors, e.g., JQ1 in inhibiting the growth of diffuse large B-cell lymphoma, acute myelogenous leukemia, and multiple myeloma cells in vitro and in mouse hematologic xenografts ( Rhyasen et al, 2016 ). AZD5153 also exhibited anti-tumorigenic functions in prostate, colorectal, and thyroid cancers and in Wilm’s tumor ( Shen et al, 2018 ; Xu et al, 2018 ; Zhang et al, 2019 ; Woods et al, 2021 ). Further, this therapy decreased the blood level of MYC RNA and increased that of HEXIM1 in a human tolerability study ( Rhyasen et al, 2016 ).…”