A20 and RBX1 Regulate Brentuximab Vedotin Sensitivity in Hodgkin Lymphoma Models

Wei, Wei; Lin, Yuquan; Song, Zhihui; Xiao, Wenming; Chen, Liqi; Yin, Jiejing; Zhou, Yan; Barta, Stefan K.; Petrus, Michael; Waldmann, Thomas A.; Yang, Yibin

doi:10.1158/1078-0432.ccr-19-4137

Cited by 22 publications

(17 citation statements)

References 46 publications

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“…S5E), in line with previous reports describing histological EBV detection associated with older HL patients 51 and fewer mutations in TNFAIP3 34 . Also, our observation may be related to the notion that EBV-infected B-cells rely on NFkB for survival 52 . In contrast to previous reports 14, 33 , we detected no association between mutational burden and EBV in our cohort (6.0 vs. 7.3 mutations/Megabase (Mb), EBV+ vs. EBV-, p=0.3418).…”

Section: Resultssupporting

confidence: 52%

Exhaustive circulating tumor DNA sequencing reveals the genomic landscape of Hodgkin lymphoma and facilitates ultrasensitive detection of minimal residual disease

Sobesky

Mammadova

Cirillo

et al. 2021

Preprint

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Individualizing treatment is key to improve outcome and reduce long-term side-effects in any cancer. In Hodgkin lymphoma (HL), individualization of treatment is hindered by a lack of genomic characterization and technology for sensitive, molecular response assessment. Sequencing of cell-free (cf)DNA is a powerful strategy to understand an individual cancer genome and can be used to develop assays for extremely sensitive disease monitoring. In HL, a high proportion of cfDNA is tumor-derived making it a highly relevant disease model to study the role of cfDNA sequencing in cancer. Here, we introduce our targeted cfDNA sequencing platform and present the largest genomic landscape of HL to date, which was entirely derived by cfDNA sequencing. We comprehensively genotype and assess minimal residual disease in 324 samples from 121 patients, presenting an integrated landscape of mutations and copy number variations in HL. In addition, we perform a deep analysis of mutational processes driving HL, investigate the clonal structure of HL and link several genotypes to HL phenotypes and outcome. Finally, we show that minimal residual disease assessment by repeat cfDNA sequencing as early as a week after treatment initiation is feasible and predicts overall treatment response allowing highly improved treatment guidance and relapse prediction. Our study also serves as a blueprint showcasing the utility of our platform for other cancers with similar therapeutic challenges.

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Section: Resultssupporting

confidence: 52%

Exhaustive circulating tumor DNA sequencing reveals the genomic landscape of Hodgkin lymphoma and facilitates ultrasensitive detection of minimal residual disease

Sobesky

Mammadova

Cirillo

et al. 2021

Preprint

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“…Linear Ubiquitin Chain Assembly Complex Is Essential for Supporting the Viability of A20 Mutant HL Lines Revealed by an E3 Ligase CRISPR Screen. To achieve a comprehensive understanding of how the ubiquitination pathway regulates HL pathogenesis, we produced a unique ubiquitin regulator-focused single-guide RNA (sgRNA) library for CRISPR library screens (18). This library covers around 10 sgRNAs per gene that are directed at 5′ constitutive exons of ∼800 human genes, including all E3 ligases, deubiquitinating enzymes, and controls.…”

Section: Resultsmentioning

confidence: 99%

Essential role of the linear ubiquitin chain assembly complex and TAK1 kinase in A20 mutant Hodgkin lymphoma

Song

Wei

Xiao

et al. 2020

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

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More than 70% of Epstein–Barr virus (EBV)-negative Hodgkin lymphoma (HL) cases display inactivation of TNFAIP3 (A20), a ubiquitin-editing protein that regulates nonproteolytic protein ubiquitination, indicating the significance of protein ubiquitination in HL pathogenesis. However, the precise mechanistic roles of A20 and the ubiquitination system remain largely unknown in this disease. Here, we performed high-throughput CRISPR screening using a ubiquitin regulator-focused single-guide RNA library in HL lines carrying either wild-type or mutant A20. Our CRISPR screening highlights the essential oncogenic role of the linear ubiquitin chain assembly complex (LUBAC) in HL lines, which overlaps with A20 inactivation status. Mechanistically, LUBAC promotes IKK/NF-κB activity and NEMO linear ubiquitination in A20 mutant HL cells, which is required for prosurvival genes and immunosuppressive molecule expression. As a tumor suppressor, A20 directly inhibits IKK activation and HL cell survival via its C-terminal linear-ubiquitin binding ZF7. Clinically, LUBAC activity is consistently elevated in most primary HL cases, and this is correlated with high NF-κB activity and low A20 expression. To further understand the complete mechanism of NF-κB activation in A20 mutant HL, we performed a specifically designed CD83-based NF-κB CRISPR screen which led us to identify TAK1 kinase as a major mediator for NF-κB activation in cells dependent on LUBAC, where the LUBAC-A20 axis regulates TAK1 and IKK complex formation. Finally, TAK1 inhibitor Takinib shows promising activity against HL in vitro and in a xenograft mouse model. Altogether, these findings provide strong support that targeting LUBAC or TAK1 could be attractive therapeutic strategies in A20 mutant HL.

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“…This trial suggested the potential benefit of BV and pembrolizumab combination therapy in patients who are heavily pretreated. Nonetheless, some patients will ultimately develop BV resistance and may partially attribute to the upregulation of NF-kappaB [ 50 ] or multidrug resistance pump (MDR1) [ 51 ]. The combination therapy of BV and cyclosporine A (an MDR1 inhibitor) was recently examined in a phase I trial (NCT03013933) to combat BV resistance in cHL, which reported an ORR of 75%, a CR rate of 42%, and a modest toxicity profile [ 51 ].…”

Section: Adcs Approved For Lymphomamentioning

confidence: 99%

Antibody-drug conjugates for the treatment of lymphoma: clinical advances and latest progress

2021

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Antibody-drug conjugates (ADCs) are a promising class of immunotherapies with the potential to specifically target tumor cells and ameliorate the therapeutic index of cytotoxic drugs. ADCs comprise monoclonal antibodies, cytotoxic payloads with inherent antitumor activity, and specialized linkers connecting the two. In recent years, three ADCs, brentuximab vedotin, polatuzumab vedotin, and loncastuximab tesirine, have been approved and are already establishing their place in lymphoma treatment. As the efficacy and safety of ADCs have moved in synchrony with advances in their design, a plethora of novel ADCs have garnered growing interest as treatments. In this review, we provide an overview of the essential elements of ADC strategies in lymphoma and elucidate the up-to-date progress, current challenges, and novel targets of ADCs in this rapidly evolving field.

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A20 and RBX1 Regulate Brentuximab Vedotin Sensitivity in Hodgkin Lymphoma Models

Cited by 22 publications

References 46 publications

Exhaustive circulating tumor DNA sequencing reveals the genomic landscape of Hodgkin lymphoma and facilitates ultrasensitive detection of minimal residual disease

Exhaustive circulating tumor DNA sequencing reveals the genomic landscape of Hodgkin lymphoma and facilitates ultrasensitive detection of minimal residual disease

Essential role of the linear ubiquitin chain assembly complex and TAK1 kinase in A20 mutant Hodgkin lymphoma

Antibody-drug conjugates for the treatment of lymphoma: clinical advances and latest progress

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