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

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.

Drug-adapted cancer cell lines as preclinical models of acquired resistance

“…Such models can be used to study processes that cannot be studied in cell lines. In this context, acquired resistance models have been established based on cell line-and patient-derived xenografts, organoids, and transgenic tumour models [115][116][117][118][119][120][121][122][123][124][125] . However, cell lines enable the establishment of a substantially larger number of models within a given timeframe and at a given cost, which is critical for studying the drug-induced heterogeneity.…”

BET inhibition in advanced cutaneous T cell lymphoma is synergistically potentiated by BCL2 inhibition or HDAC inhibition

“…Other BET inhibitors have been shown to upregulate BIM in AML cells and melanoma [ 51 , 66 ]. BIM has been suggested to play a key role in the mechanism of synergy between BET inhibition and BCL2 inhibition in primary double-hit lymphoma cells, and SCLC [ 71 , 72 ]. BIM binds BCL2, altering the balance between pro-apoptotic and anti-apoptotic signals.…”

BFL-1 expression determines the efficacy of venetoclax in MYC+/BCL2+ double hit lymphoma

“…First-line treatment of DHL patients is based on immunochemotherapy and intensive treatment strategies, but it does not produce a sustained remission in the majority of the cases [ 3 ]. While short-time exposure to venetoclax can trigger significant antitumoral effect in DHL cultures [ 4 ], we recently reported that prolonged exposure to the compound was associated with a decreased response of DHL cell lines at all the doses used [ 5 ]. This phenomenon was not seen in cell lines of B-cell germinal center (GCB)-diffuse large B cell lymphoma (DLBCL) origin with no concurrent MYC and BCL-2, suggesting differential compensatory mechanisms between the two NHL subtypes.…”