論文 - 詳細
| RRC ID | 82450 |
|---|---|
| 著者 | Sasaki M, Kato D, Yoshida H, Shimizu T, Ogiwara H. |
| タイトル | Efficacy of CBP/p300 Dual Inhibitors against De-repression of KREMEN2 in cBAF-Deficient Cancers. |
| ジャーナル | Cancer Res Commun |
| Abstract |
The SWI/SNF chromatin remodeling complex is divided into three subcomplexes: cBAF, PBAF, and ncBAF. Constituent genes (e.g., SMARCB1, SMARCA4, SMARCA2, and SS18) of the SWI/SNF complex often harbor genetic abnormalities in various cancers. Previously, we found that histone acetyltransferases CBP/p300 dual inhibitors could be promising treatments for SMARCB1-deficient cancers. We show that treatment with CBP/p300 dual inhibitors causes synthetic lethality in cBAF-deficient cancers such as SMARCA4/SMARCA2-deficient and SS18-SSX fusion cancers. Given the sensitivity to CBP/p300 dual inhibitors and their commonality with SWI/SNF subcomplexes containing each subunit, CBP/p300 dual inhibitors could be promising treatments for cancers harboring abnormalities in constituent genes included in the entire cBAF subcomplex. Since SMARCA4/SMARCA2-deficient and SS18-SSX fusion cancer cells depend on transcriptional upregulation of KREMEN2 due to SMARCA4/SMARCA2-deficiency and SS18-SSX fusion, we clarified that synthetic lethality is induced by repressing expression of KREMEN2 by simultaneous inhibition of CBP/p300. In addition, simultaneous inhibition of CBP/p300 led to transcriptional downregulation of KREMEN2, followed by apoptosis induction via KREMEN1. Furthermore, treatment with CBP/p300 dual inhibitor suppressed the growth of xenografts derived from SMARCA4/SMARCA2-deficient and SS18-SSX fusion cancer cells, resulting from repression of KREMEN2 and induction of apoptosis. Thus, CBP/p300 dual inhibitors could be promising for SMARCA4/SMARCA2-deficient lung cancer and SS18-SSX fusion synovial sarcoma, which are entirely deficient in the cBAF complex. |
| 公開日 | 2024-12-3 |
| DOI | 10.1158/2767-9764.CRC-24-0484 |
| PII | 750389 |
| PMID | 39625239 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 6 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | Aska-SS(RCB3576) HS-SY-II(RCB2231) OS-RC-2(RCB0735) |