Reference - Detail
| RRC ID | 67172 |
|---|---|
| Author | 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. |
| Title | 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. |
| Journal | 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. |
| Volume | 37(14) |
| Pages | 1830-1844 |
| Published | 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 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | Patent(IFI CLAIMS) |
| Total number of mentions | 18 |
| Altmetric score changes over past 6months | 3.0 |
| Resource | |
| Human and Animal Cells | StromaNKtert(RCB2350) |