ARID2 is a pomalidomide-dependent CRL4CRBN substrate in multiple myeloma cells

Yamamoto, Junichi; Suwa, Tetsufumi; Murase, Yuki; Tateno, Shumpei; Mizutome, Hirotaka; Asatsuma‐Okumura, Tomoko; Shimizu, Nobuyuki; Kishi, Takashi; Momose, Shuji; Kizaki, Masahiro; Ito, Takumi; Yamaguchi, Yuki; Handa, Hiroshi

doi:10.1038/s41589-020-0645-3

Cited by 63 publications

(52 citation statements)

References 41 publications

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“…For instance, in IMiD-resistant tumor cells, the levels of CRBN are reduced; however, residual CRBN levels in LEN-resistant cells have been shown to be sufficient for POM to maintain functionality [28]. Moreover, POM has higher affinity for CRBN; is twice as potent as LEN in the degradation of Ikaros [30]; and is more effective in degrading ARID2, a substrate of CRL4 CRBN [14]. Gene expression profiling in xenograft tumor cells following treatment with LEN/Dex or POM/Dex showed that they induce differential gene expression patterns, including some shared but also many unique downstream targets [29].…”

Section: Discussionmentioning

confidence: 99%

“…Pomalidomide is more potent than LEN and thalidomide against CRBN and displays distinct immune modulating properties. In addition, POM is more effective than LEN in ubiquitinating ARID2, a substrate of CRBN CRL4 and a component of the polybromo-associated BAF chromatin-remodeling complex, leading to its degradation, which in turn inhibits MYC expression and proliferation [14]. Interestingly, POM has demonstrated activity in in vitro and in vivo models of LEN resistance [7].…”

Section: Introductionmentioning

confidence: 99%

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Pomalidomide Plus Low-Dose Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients: Results of the Real-World “POWERFUL” Study

Terpos

Repousis

Lalayanni

et al. 2021

JCM

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The “POWERFUL” multicenter, retrospective, and prospective study investigated the effectiveness of pomalidomide plus low-dose dexamethasone (POM/LoDex) therapy in relapsed/refractory multiple myeloma in routine care in Greece. Ninety-nine eligible adult patients treated with POM/LoDex according to the approved label after having received ≥2 prior therapies, including lenalidomide and bortezomib, were consecutively enrolled between 16 November 2017 and 21 February 2019 in 18 hematology departments. Fifty patients (50.5%) started POM/LoDex as third-line treatment. During the treatment period (median: 8.3 months; range: 0.3–47.6 months), the median POM dose was 4 mg/day, and 31.3% of the patients received additional antimyeloma agents. The overall response rate was 32.3%. During a median follow-up period of 13.8 months (Kaplan–Meier estimate), the median progression-free survival (PFS) was 10.5 months (95% CI: 7.4–14.4). The PFS was not significantly different between patients receiving POM/LoDex in the third versus later line of therapy, nor between patients receiving concomitant antimyeloma therapy versus POM/LoDEx doublet. During the prospective safety data collection period (median: 7.6 months) among patients with prospective follow-up (N = 75), POM-related adverse event incidence rate was 42.7% (serious: 18.7%; grade ≥ 3 hematological POM-related adverse events: 8.0%). Only neutropenia (13.3%) was reported at a frequency ≥10%. In conclusion, in this real-world study, POM/LoDex displayed a long PFS with no new safety signals emerging.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pomalidomide Plus Low-Dose Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients: Results of the Real-World “POWERFUL” Study

Terpos

Repousis

Lalayanni

et al. 2021

JCM

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“…Deletion of CSN causes a significant decrease in CRBN protein levels in MM cells, which can explain the IMiD resistance in CSN-deleted cells [ 38 ]. AT-rich interactive domain 2 (ARID2), a component of the polybromo-BRG1-associated factors (PBAF) chromatin-remodeling complex, was also identified to be required for pomalidomide activity in MM cells [ 38 ], which was recently verified by the discovery of ARID2 as a pomalidomide-induced neosubstrate [ 113 ]. Degradation of ARID2 causes downregulation of MYC, leading to the death of MM cells [ 113 ].…”

Section: Genome-wide Crispr Screenings As a Tool To Identify Genes Required For Imid Sensitivitymentioning

confidence: 99%

“…AT-rich interactive domain 2 (ARID2), a component of the polybromo-BRG1-associated factors (PBAF) chromatin-remodeling complex, was also identified to be required for pomalidomide activity in MM cells [ 38 ], which was recently verified by the discovery of ARID2 as a pomalidomide-induced neosubstrate [ 113 ]. Degradation of ARID2 causes downregulation of MYC, leading to the death of MM cells [ 113 ]. These data demonstrate the powerful function of CRISPR screens in the discovery of regulatory networks of drug sensitivity.…”

Section: Genome-wide Crispr Screenings As a Tool To Identify Genes Required For Imid Sensitivitymentioning

confidence: 99%

Key regulators of sensitivity to immunomodulatory drugs in cancer treatment

Wang

Gao

2021

Biomark Res

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Immunomodulatory drugs (IMiDs) include thalidomide, lenalidomide, and pomalidomide, which have shown significant efficacy in the treatment of multiple myeloma (MM), myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)) and other hematological malignancies. IMiDs hijack the CRL4CRBN ubiquitin ligase to target cellular proteins for ubiquitination and degradation, which is responsible for their clinical activity in MM and MDS with del(5q). However, intrinsic and acquired resistance frequently limit the efficacy of IMiDs. Recently, many efforts have been made to explore key regulators of IMiD sensitivity, resulting in great advances in the understanding of the regulatory networks related to this class of drugs. In this review, we describe the mechanism of IMiDs in cancer treatment and summarize the key regulators of IMiD sensitivity. Furthermore, we introduce genome-wide CRISPR-Cas9 screenings, through which the regulatory networks of IMiD sensitivity could be identified.

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“…In 2010, pomalidomide and its analogs immunomodulatory imide drugs (IMiDs) have been defined as molecule glues to bind with the endogenous cereblon (CRBN) E3 ligase ( Ito et al, 2010 ; Fischer et al, 2014 ), subsequently causing the proteasomal degradation of several neo-substrates, including IKZFs ( Kronke et al, 2014 ; Lu et al, 2014 ), CK1α ( Kronke et al, 2015 ), GSPT1 ( Matyskiela et al, 2016 ), SALL4 ( Donovan et al, 2018 ), p63 ( Asatsuma-Okumura et al, 2019 ) and ARID2 ( Yamamoto et al, 2020 ). In 2015, IMiDs as ligands of the CRBN E3 ligase have been firstly used to develop CRBN-based PROTACs for the degradation of BRD4 and FKBP12 ( Winter et al, 2015 ), and to date CRBN-based PROTACs have been applied to more than 30 different protein targets, for the treatment of cancer and inflammation disease ( Supplementary Table 1 ; Mullard, 2021 ), among which ARV-110 ( Neklesa et al, 2018 ) (NCT03888612) and ARV471 ( Flanagan et al, 2019 ) (NCT04072952) are in Phase I/II clinical trials for the treatment of prostate cancer ( Petrylak et al, 2020 ) and breast cancer (BRCA), respectively.…”

Section: Introductionmentioning

confidence: 99%

Light-Controllable PROTACs for Temporospatial Control of Protein Degradation

Liu

Peng

Wei

2021

Front. Cell Dev. Biol.

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PROteolysis-TArgeting Chimeras (PROTACs) is an emerging and promising approach to target intracellular proteins for ubiquitination-mediated degradation, including those so-called undruggable protein targets, such as transcriptional factors and scaffold proteins. To date, plenty of PROTACs have been developed to degrade various disease-relevant proteins, such as estrogen receptor (ER), androgen receptor (AR), RTK, and CDKs. However, the on-target off-tissue and off-target effect is one of the major limitation that prevents the usage of PROTACs in clinic. To this end, we and several other groups have recently developed light-controllable PROTACs, as the representative for the third generation controllable PROTACs, by using either photo-caging or photo-switch approaches. In this review, we summarize the emerging light-controllable PROTACs and the prospective for other potential ways to achieve temporospatial control of PROTACs.

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ARID2 is a pomalidomide-dependent CRL4CRBN substrate in multiple myeloma cells

Cited by 63 publications

References 41 publications

Pomalidomide Plus Low-Dose Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients: Results of the Real-World “POWERFUL” Study

Pomalidomide Plus Low-Dose Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients: Results of the Real-World “POWERFUL” Study

Key regulators of sensitivity to immunomodulatory drugs in cancer treatment

Light-Controllable PROTACs for Temporospatial Control of Protein Degradation

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