論文 - 詳細
| RRC ID | 60107 |
|---|---|
| 著者 | Shorstova T, Marques M, Su J, Johnston J, Kleinman CL, Hamel N, Huang S, Alaoui-Jamali MA, Foulkes WD, Witcher M. |
| タイトル | SWI/SNF-Compromised Cancers Are Susceptible to Bromodomain Inhibitors. |
| ジャーナル | Cancer Res |
| Abstract |
The antitumor activity of bromodomain and extraterminal motif protein inhibitors (BETi) has been demonstrated across numerous types of cancer. As such, these inhibitors are currently undergoing widespread clinical evaluation. However, predictive biomarkers allowing the stratification of tumors into responders and nonresponders to BETi are lacking. Here, we showed significant antiproliferative effects of low dosage BETi in vitro and in vivo against aggressive ovarian and lung cancer models lacking SMARCA4 and SMARCA2, key components of SWI/SNF chromatin remodeling complexes. Restoration of SMARCA4 or SMARCA2 promoted resistance to BETi in these models and, conversely, knockdown of SMARCA4 sensitized resistant cells to BETi. Transcriptomic analysis revealed that exposure to BETi potently downregulated a network of genes involved in receptor tyrosine kinase (RTK) signaling in SMARCA4/A2-deficient cells, including the oncogenic RTK HER3. Repression of signaling downstream of HER3 was found to be an important determinant of response to BETi in SMARCA4/A2-deficient cells. Overall, we propose that BETi represent a rational therapeutic strategy in poor-prognosis, SMARCA4/A2-deficient cancers. SIGNIFICANCE: These findings address an unmet clinical need by identifying loss of SMARCA4/A2 as biomarkers of hypersensitivity to BETi. |
| 巻・号 | 79(10) |
| ページ | 2761-2774 |
| 公開日 | 2019-5-15 |
| DOI | 10.1158/0008-5472.CAN-18-1545 |
| PII | 0008-5472.CAN-18-1545 |
| PMID | 30877105 |
| MeSH | Animals Biomarkers, Tumor Cell Line, Tumor Chromatin Assembly and Disassembly DNA Helicases / metabolism* Female HEK293 Cells Heterografts Humans Mice Mice, Inbred NOD Mice, SCID Neoplasms / metabolism* Neoplasms / pathology Nuclear Proteins / metabolism* Signal Transduction Transcription Factors / metabolism* |
| IF | 8.378 |
| 引用数 | 9 |
| 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 | 3 |
| 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 | OVK18(RCB1903) |