Acquired resistance to ABT-737 in lymphoma cells that up-regulate MCL-1 and BFL-1

Yecies, Derek; Carlson, Nicole E.; Deng, Jing; Letaï, Anthony

doi:10.1182/blood-2009-07-233304

Cited by 317 publications

(317 citation statements)

References 41 publications

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“…One would be to include compounds that decrease Mcl-1 expression (such as ABT-737 treatment in combination with flavopiridol or ara-C) and another approach would be to inhibit Mcl-1 antiapoptotic action by increasing Noxa expression using bortezomib. Recent publications suggested that ABT-737 exposure might enhance Mcl-1 upregulation, leading to ABT-737 resistance (36,42). This putative role played by ABT-737 as a Mcl-1 upregulator further enhances the potential of Mcl-1-targeted therapy used in combination with ABT-737.…”

Section: Discussionmentioning

confidence: 99%

ABT-737 Induces Apoptosis in Mantle Cell Lymphoma Cells with a Bcl-2high/Mcl-1low Profile and Synergizes with Other Antineoplastic Agents

Touzeau

Dousset

Bodet

et al. 2011

Clinical Cancer Research

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Purpose: Mantle cell lymphoma (MCL) is considered to be incurable. ABT-737 is a BH3 mimetic that targets Bcl-2, which is overexpressed in MCL and implicated in drug resistance. The present work investigated the antitumor effect of ABT-737. Experimental Design: Six MCL cell lines and primary MCL cells (n = 13) were used. Sensitivity to ABT-737 was assessed, and expression levels of Bcl-2 and Mcl-1 were analyzed. Finally, ABT-737 was combined with other cytotoxic agents to promote tailored therapy. Results: MINO and GRANTA-519 cell lines were highly sensitive to ABT-737 [the median lethal dose (LD50) = 20 and 80 nmol/L, respectively], whereas other cell lines were resistant. In primary MCL cells, 46% of patients' samples were sensitive to ABT-737. The analysis of protein expression levels revealed that both sensitive cell lines and primary MCL cells could be characterized by a Bcl-2high/Mcl-1low profile, whereas resistant MCL cells contained high levels of Mcl-1. ABT-737 induced a rapid disruption of both Bcl-2/Bax and Bcl-2/Bik complexes. In addition, silencing of Mcl-1 by siRNA sensitized MCL cell lines to ABT-737. Similarly, flavopiridol, which induces Mcl-1 downregulation, in combination with ABT-737 led to a synergistic anti-MCL effect in ABT-737–resistant cell lines. This synergy was also observed when ABT-737 was combined with either bortezomib or cytarabine. Conclusions: The present work shows that ABT-737 induces strong apoptosis in MCL cells expressing a Bcl-2high/Mcl-1low profile. In ABT-737–resistant MCL cells, downregulation of Mcl-1 overcomes Mcl-1–induced resistance and synergizes ABT-737 effects. Our results strongly support the use of ABT-737 according to the Bcl-2/Mcl-1 tumor cell profiles in the treatment of MCL. Clin Cancer Res; 17(18); 5973–81. ©2011 AACR.

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Section: Discussionmentioning

confidence: 99%

ABT-737 Induces Apoptosis in Mantle Cell Lymphoma Cells with a Bcl-2high/Mcl-1low Profile and Synergizes with Other Antineoplastic Agents

Touzeau

Dousset

Bodet

et al. 2011

Clinical Cancer Research

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“…Indeed, ABT-737 and its orally active analog, ABT-263, have a single agent activity in a subset of cancers (including multiple myeloma and small-cell lung cancer) that rely on Bcl-2/Bcl-X L but not Mcl-1 for survival (7). However, recent studies demonstrated that cancer cells rapidly develop resistance to ABT-737 through up-regulation of Mcl-1 and that down-regulation of Mcl-1 restores the sensitivity to ABT-737 (38,44). This suggests that the anti-apoptotic members of the Bcl-2 family can functionally compensate for each other.…”

Section: Discussionmentioning

confidence: 99%

Discovery of Marinopyrrole A (Maritoclax) as a Selective Mcl-1 Antagonist that Overcomes ABT-737 Resistance by Binding to and Targeting Mcl-1 for Proteasomal Degradation

Doi

Sung

et al. 2012

Journal of Biological Chemistry

141

177

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“…24 The emergence of Bcl-2 inhibitors such as ABT-263 and ABT-199 are showing considerable promise for the treatment of CLL, however these drugs are unable to inhibit the antiapoptotic effects of Mcl-1 conferred by the microenvironment, 25 thus identifying a known mechanism of resistance to these BH3-mimetics. [26][27][28][29] Several pan-Bcl-2 family inhibitors such as obatoclax, sabutoclax and AT-101 have been developed with low micromolar potency against Mcl-1. Obatoclax (a BH-3 mimetic) has been investigated in a phase I clinical trial for advanced CLL, but its effect was limited.…”

Section: Introductionmentioning

confidence: 99%

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1

et al. 2015

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The pro-survival Bcl-2 family member Mcl-1 is expressed in chronic lymphocytic leukemia (CLL), with high expression correlated with progressive disease. The spliceosome inhibitor spliceostatin A (SSA), is known to regulate Mcl-1 and so here we assessed the ability of SSA to elicit apoptosis in CLL. SSA induced apoptosis of CLL cells at low nanomolar concentrations in a dose-and time-dependent manner, but independently of SF3B1 mutational status, IGHV status and CD38 or ZAP70 expression.However, normal B and T cells were less sensitive than CLL cells (p=0.006 and p<0.001, respectively).

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Acquired resistance to ABT-737 in lymphoma cells that up-regulate MCL-1 and BFL-1

Cited by 317 publications

References 41 publications

ABT-737 Induces Apoptosis in Mantle Cell Lymphoma Cells with a Bcl-2high/Mcl-1low Profile and Synergizes with Other Antineoplastic Agents

ABT-737 Induces Apoptosis in Mantle Cell Lymphoma Cells with a Bcl-2high/Mcl-1low Profile and Synergizes with Other Antineoplastic Agents

Discovery of Marinopyrrole A (Maritoclax) as a Selective Mcl-1 Antagonist that Overcomes ABT-737 Resistance by Binding to and Targeting Mcl-1 for Proteasomal Degradation

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1

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