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

Esteve-Arenys, Anna; Valero, Juan García; Chamorro-Jorganes, Aránzazu; Gonzalez, David G.; Rodríguez, Vanina; Dlouhy, Iván; Salaverría, Itziar; Campo, Elı́as; Colomer, Dolors; Martı́nez, Antonio; Rymkiewicz, Grzegorz; Pérez-Galán, Patricia; López‐Guillermo, Armando; Roué, Gaël

doi:10.1038/s41388-017-0111-1

Cited by 72 publications

(63 citation statements)

References 45 publications

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“…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.…”

Section: Resultsmentioning

confidence: 99%

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

Michaelis¹,

Wass²,

Činátl³

2019

CDR

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Acquired resistance formation limits the efficacy of anti-cancer therapies. Acquired and intrinsic resistance differ conceptually. Acquired resistance is the consequence of directed evolution, whereas intrinsic resistance depends on the (stochastic) presence of pre-existing resistance mechanisms. Preclinical model systems are needed to study acquired drug resistance because they enable: (1) in depth functional studies; (2) the investigation of non-standard treatments for a certain disease condition (which is necessary to identify small groups of responders); and (3) the comparison of multiple therapies in the same system. Hence, they complement data derived from clinical trials and clinical specimens, including liquid biopsies. Many groups have successfully used drug-adapted cancer cell lines to identify and elucidate clinically relevant resistance mechanisms to targeted and cytotoxic anti-cancer drugs. Hence, we argue that drug-adapted cancer cell lines represent a preclinical model system in their own right that is complementary to other preclinical model systems and clinical data.

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Section: Resultsmentioning

confidence: 99%

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

Michaelis¹,

Wass²,

Činátl³

2019

CDR

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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While several systemic therapies are approved for cutaneous T cell lymphoma (CTCL), a non-Hodgkin lymphoma of skin-homing T cells that may involve lymph nodes and peripheral blood in advanced stages, relapses are common. Mutational analysis of CTCL cells has revealed frequent amplification of the MYC oncogene, and bromodomain and extraterminal (BET) protein inhibitors have been shown to repress MYC expression in various malignancies. Towards a potential novel therapy, we thus sought to examine the effect of BET inhibition on CTCL cells in vitro. Each of the four tested BET inhibitors (JQ1, ABBV-075, I-BET762, CPI-0610) consistently induced dose-dependent decreases in viability of isolated patient-derived CTCL cells and established CTCL cell lines (MyLa, Sez4, HH, Hut78). This effect was synergistically potentiated by combination of BET inhibition with BCL2 inhibition (e.g. venetoclax) or histone deacetylase (HDAC) inhibition (e.g. vorinostat or romidepsin). There was also a marked increase in caspase 3/7 activation when JQ1 was combined with either vorinostat or romidepsin, confirming that the observed synergies are due in major part to induction of apoptosis. Furthermore, MYC and BCL2 expression were each synergistically repressed when CTCL cells were treated with JQ1 plus HDAC inhibitors, suggesting cooperative activities at the level of epigenetic regulation. Taken together, these data indicate that targeting BET proteins in CTCL represents a promising novel therapeutic strategy that may be substantially potentiated by combination with BCL2 or HDAC inhibition.

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“…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.…”

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confidence: 99%