ABT-199, a BH3 mimetic that specifically targets Bcl-2, enhances the antitumor activity of chemotherapy, bortezomib and JQ1 in “double hit” lymphoma cells

Johnson-Farley, Nadine; Veliz, Jonny; Bhagavathi, Sharathkumar; Bertino, Joseph R.

doi:10.3109/10428194.2014.981172

Cited by 65 publications

(53 citation statements)

References 20 publications

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“…80 Combination of venetoclax with doxorubicin or cytarabine, bortezomib, and JQ1 produced synergistic cell kill against the double-hit lymphoma cell lines cultured in vitro. 81 In vitro and in vivo results also supported that radiotherapy could synergize with venetoclax for treatment of DLBCL and MCL. 82 All the above studies provide evidence for the feasibility of future combination therapy options.…”

supporting

confidence: 55%

Development of venetoclax for therapy of lymphoid malignancies

Zhu

Almasan

2017

DDDT

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B-cell lymphoma-2 (BCL-2) family dysfunction and impairment of apoptosis are common in most B-cell lymphoid malignancies. Venetoclax (Venclexta™, formerly ABT-199, GDC-0199) is a highly selective BCL-2 inhibitor, which mimics its BCL-2 homology 3-domain to induce apoptosis. It was approved for treatment of previously treated chronic lymphocytic leukemia (CLL) patients with 17p deletion early in 2016. It has also been in clinical trials for other B-cell lymphoid malignancies. Unlike the other recently approved targeted agents idelalisib and ibrutinib, so far there has been no relapse reported in some patients. Also, unlike the other targeted agents, it is effective against tumor cells that reside in the blood marrow. Despite its promising outcome in CLL, preclinical data have already uncovered mechanistic insights underlying venetoclax resistance, such as upregulation of MCL-1 or BCL-xL expression and protective signaling from the microenvironment. In this review, we describe the role of the BCL-2 family in the pathogenesis of B-cell lymphoid malignancies, the development of venetoclax, and its current clinical outcome in CLL and other B-cell malignancies. We also discuss the resistance mechanisms that develop following venetoclax therapy, potential strategies to overcome them, and how this knowledge can be translated into clinical applications.

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supporting

confidence: 55%

Development of venetoclax for therapy of lymphoid malignancies

Zhu

Almasan

2017

DDDT

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“…In both models, the degree of apoptosis induction in tolerant cells cotreated with CPI203 and ABT-737 was comparable with parental cells treated with BETi alone, suggesting that pharmacologic inhibition of BCL2 family members can abrogate tolerance to BETi. Notably, combination of the BET inhibitor JQ1 with ABT-199 showed synergistic effects on growth inhibition (13), highlighting the potential of combining BETi with BH3 peptidomimetics.…”

Section: Resultsmentioning

confidence: 99%

Preclinical Anticancer Efficacy of BET Bromodomain Inhibitors Is Determined by the Apoptotic Response

et al. 2016

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Small-molecule inhibitors of the bromodomain and extraterminal (BET) family of proteins are being tested in clinical trials for a variety of cancers, but patient selection strategies remain limited. This challenge is partly attributed to the heterogeneous responses elicited by BET inhibition (BETi), including cellular differentiation, senescence, and death. In this study, we performed phenotypic and gene-expression analyses of treatment-naive and engineered tolerant cell lines representing human melanoma and leukemia to elucidate the dominant features defining response to BETi. We found that de novo and acquired tolerance to BETi is driven by the robustness of the apoptotic response, and that genetic or pharmacologic manipulation of the apoptotic signaling network can modify the phenotypic response to BETi. We further reveal that the expression signatures of the apoptotic genes BCL2, BCL2L1, and BAD significantly predict response to BETi. Taken together, our findings highlight the apoptotic program as a determinant of response to BETi, and provide a molecular basis for patient stratification and combination therapy development.

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“…Both Bcl-2 and Bcl-X L function to dampen the apoptotic response by hindering Bax-Bak mediated perforation of the mitochondrial outer membrane, thus preventing cytochrome-c release and activation of the caspase cascade. Several groups have reported that the anti-tumour effect of bortezomib is greatly enhanced by antagonists of Bcl-2 function (Johnson-Farley et al, 2015;Kunami et al, 2014;Paoluzzi et al, 2008;Reuland et al, 2012). The Bcl-2 inhibitors ABT-737 and ABT-199 respectively enhance the cytotoxicity of bortezomib in adult T-cell leukaemia/lymphoma (Kunami et al, 2014) and "double hit" lymphoma cells (Johnson-Farley et al, 2015).…”

Section: Mechanisms Of Resistance To Bortezomib and Other Inhibitors mentioning

confidence: 99%

Inhibition of proteasome deubiquitinase activity: a strategy to overcome resistance to conventional proteasome inhibitors?

Selvaraju

Mazurkiewicz

Wang

et al. 2015

Drug Resistance Updates

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The ubiquitin-proteasome system (UPS) is the primary mechanism controlling the degradation of damaged, unwanted or short-lived proteins in eukaryotic cells. In addition to protein homeostasis, the UPS has also emerged as a critical node in the regulation of signalling pathways implicated in the growth and survival of cancer cells. The absolute dependency of cancer cells on a functioning UPS has been exploited in the development of anti-cancer therapies as exemplified by development of proteasome inhibitors for the treatment of certain leukemic malignancies.Deubiquitinases (DUBs) are enzyme components of the UPS that catalyse re-editing of poly ubiquitin chains and/or removal of ubiquitin en bloc from target substrates leading to alterations in protein stability and/or downstream signalling. There is a growing recognition that targeting DUB activity may be a feasible option for the development of novel anti-cancer therapies. In particular inhibition of proteasomal cysteine DUBs (i.e. USP14 and UCHL5) has been shown to be particularly cytotoxic to cancer cells leading to the accumulation of ubiquitinated proteins and proteotoxic stress. In this review we focus on the mechanisms of action of proteasome DUB inhibitors as well as the potential of such compounds to circumvent acquired drug resistance in cancer patients.

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ABT-199, a BH3 mimetic that specifically targets Bcl-2, enhances the antitumor activity of chemotherapy, bortezomib and JQ1 in “double hit” lymphoma cells

Cited by 65 publications

References 20 publications

Development of venetoclax for therapy of lymphoid malignancies

Development of venetoclax for therapy of lymphoid malignancies

Preclinical Anticancer Efficacy of BET Bromodomain Inhibitors Is Determined by the Apoptotic Response

Inhibition of proteasome deubiquitinase activity: a strategy to overcome resistance to conventional proteasome inhibitors?

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