| RRC ID |
67172
|
| 著者 |
Esteve-Arenys A, Valero JG, Chamorro-Jorganes A, Gonzalez D, Rodriguez V, Dlouhy I, Salaverria I, Campo E, Colomer D, Martinez A, Rymkiewicz G, Pérez-Galán P, Lopez-Guillermo A, Roué G.
|
| タイトル |
The BET bromodomain inhibitor CPI203 overcomes resistance to ABT-199 (venetoclax) by downregulation of BFL-1/A1 in in vitro and in vivo models of MYC+/BCL2+ double hit lymphoma.
|
| ジャーナル |
Oncogene
|
| Abstract |
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, mostly known as double-hit lymphoma (DHL), is a rare entity characterized by morphologic and molecular features between Burkitt lymphoma and the clinically manageable diffuse large B-cell lymphoma (DLBCL). DHL patients usually undergo a rapidly progressing clinical course associated with resistance to standard chemo-immunotherapy. As a consequence, the prognosis of this entity is particularly poor with a median overall survival inferior to 1 year. ABT-199 (venetoclax) is a potent and selective small-molecule antagonist of BCL-2 recently approved for the treatment of a specific subtype of lymphoid neoplasm. In this study, we demonstrate that single-agent ABT-199 efficiently displaces BAX from BCL-2 complexes but fails to maintain a significant antitumor activity over time in most MYC+/BCL2+DHL cell lines and primary cultures, as well as in a xenograft mouse model of the disease. We further identify the accumulation of the BCL2-like protein BFL-1 to be a major mechanism involved in acquired resistance to ABT-199. Noteworthy, this phenomenon can be counteracted by the BET bromodomain inhibitor CPI203, since gene expression profiling identifies BCL2A1, the BFL-1 coding gene, as one of the top apoptosis-related gene modulated by this compound. Upon CPI203 treatment, simultaneous downregulation of MYC and BFL-1 further overcomes resistance to ABT-199 both in vitro and in vivo, engaging synergistic caspase-mediated apoptosis in DHL cultures and tumor xenografts. Together, these findings highlight the relevance of BFL-1 in DH lymphoma-associated drug resistance and support the combined use of a BCL-2 antagonist and a BET inhibitor as a promising therapeutic strategy for patients with aggressive DHL.
|
| 巻・号 |
37(14)
|
| ページ |
1830-1844
|
| 公開日 |
2018-4-1
|
| DOI |
10.1038/s41388-017-0111-1
|
| PII |
10.1038/s41388-017-0111-1
|
| PMID |
29353886
|
| MeSH |
Acetamides / pharmacology*
Animals
Azepines / pharmacology*
Bridged Bicyclo Compounds, Heterocyclic / therapeutic use*
Cell Line, Tumor
Down-Regulation / drug effects
Down-Regulation / genetics
Drug Resistance, Neoplasm / drug effects*
Drug Resistance, Neoplasm / genetics
Drug Synergism
Gene Expression Regulation, Neoplastic / drug effects
Gene Knockdown Techniques
Humans
Lymphoma / drug therapy*
Lymphoma / genetics
Lymphoma / pathology
Mice
Mice, Inbred C57BL
Mice, SCID
Mice, Transgenic
Minor Histocompatibility Antigens / genetics*
Proto-Oncogene Proteins c-bcl-2 / genetics*
Proto-Oncogene Proteins c-myc / genetics*
Sulfonamides / therapeutic use*
Xenograft Model Antitumor Assays
|
| IF |
7.971
|
| リソース情報 |
| ヒト・動物細胞 |
StromaNKtert(RCB2350) |
