論文 - 詳細
| RRC ID | 61659 |
|---|---|
| 著者 | Okonska A, Bühler S, Rao V, Ronner M, Blijlevens M, van der Meulen-Muileman IH, de Menezes RX, Wipplinger M, Oehl K, Smit EF, Weder W, Stahel RA, Penengo L, van Beusechem VW, Felley-Bosco E. |
| タイトル | Functional Genomic Screen in Mesothelioma Reveals that Loss of Function of BRCA1-Associated Protein 1 Induces Chemoresistance to Ribonucleotide Reductase Inhibition. |
| ジャーナル | Mol Cancer Ther |
| Abstract |
Loss of function of BRCA1-associated protein 1 (BAP1) is observed in about 50% of malignant pleural mesothelioma (MPM) cases. The aim of this study was to investigate whether this aspect could be exploited for targeted therapy. A genetically engineered model was established expressing either functional or nonfunctional BAP1, and whole-genome siRNA synthetic lethality screens were performed assessing differentially impaired survival between the two cell lines. The whole-genome siRNA screen unexpectedly revealed 11 hits (FDR < 0.05) that were more cytotoxic to BAP1-proficient cells. Two actionable targets, ribonucleotide reductase (RNR) catalytic subunit M1 (RRM1) and RNR regulatory subunit M2 (RRM2), were validated. In line with the screen results, primary mesothelioma (BAP1+/-) overexpressing BAP1 C91A (catalytically dead mutant) was more resistant to RNR inhibition, while BAP1 knockdown in the BAP1-proficient cell lines rescued the cells from their vulnerability to RNR depletion. Gemcitabine and hydroxyurea were more cytotoxic in BAP1-proficient cell line-derived spheroids compared with BAP1 deficient. Upregulation of RRM2 upon gemcitabine and hydroxyurea treatment was more profound in BAP1 mut/del cell lines. Increased lethality mediated by RNR inhibition was observed in NCI-H2452 cells reconstituted with BAP1-WT but not with BAP1 C91A. Upregulation of RRM2 in NCI-H2452-BAP1 WT spheroids was modest compared with control or C91A mutant. Together, we found that BAP1 is involved in the regulation of RNR levels during replication stress. Our observations reveal a potential clinical application where BAP1 status could serve as predictive or stratification biomarker for RNR inhibition-based therapy in MPM. |
| 巻・号 | 19(2) |
| ページ | 552-563 |
| 公開日 | 2020-2-1 |
| DOI | 10.1158/1535-7163.MCT-19-0356 |
| PII | 1535-7163.MCT-19-0356 |
| PMID | 31619462 |
| MeSH | Antimetabolites, Antineoplastic / pharmacology Cell Line, Tumor Deoxycytidine / analogs & derivatives Deoxycytidine / pharmacology Drug Resistance, Neoplasm Enzyme Inhibitors / pharmacology Gemcitabine Gene Knockdown Techniques Genomics Humans Hydroxyurea / pharmacology Mesothelioma / drug therapy* Mesothelioma / enzymology Mesothelioma / genetics* Pleural Neoplasms / drug therapy Pleural Neoplasms / enzymology Pleural Neoplasms / genetics* Ribonucleoside Diphosphate Reductase / antagonists & inhibitors* Ribonucleoside Diphosphate Reductase / genetics Ribonucleoside Diphosphate Reductase / metabolism Transfection Tumor Suppressor Proteins / genetics* Tumor Suppressor Proteins / metabolism Ubiquitin Thiolesterase / genetics* Ubiquitin Thiolesterase / metabolism |
| IF | 5.615 |
| 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 | ACC-MESO-1(RCB2292) ACC-MESO-4(RCB2293) |