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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

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

A Esteve-Arenys, J G Valero, A Chamorro-Jorganes, D Gonzalez, V Rodriguez, I Dlouhy, I Salaverria, E Campo, D Colomer, A Martinez, G Rymkiewicz, P Pérez-Galán, A Lopez-Guillermo, G Roué

Oncogene. 2018 Apr;37(14):1830-1844.

PMID: 29353886

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1446144042	CPI203		1446144-04-2	Price

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