Hierarchy for targeting prosurvival BCL2 family proteins in multiple myeloma: pivotal role of MCL1

Gong, Juanqin; Khong, Tiffany; Segal, David; Yao, Yuan; Riffkin, Christopher D.; Garnier, Jean Marc; Khaw, Seong Lin; Lessène, Guillaume; Spencer, Andrew; Herold, Marco J.; Roberts, Andrew W.; Huang, David C.S.

doi:10.1182/blood-2016-03-704908

Cited by 131 publications

(114 citation statements)

References 49 publications

(96 reference statements)

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“…BH3 profiling identified subsets of MM cell lines and primary MM cells dependent on either BCL-2 alone or on BCL-2 and BCL-X L together (86). Gong et al also identified a sub-set of MM cell lines that were highly dependent on BCL-X L (87). Similar observations were made by Punnoose and colleagues, whose chemical parsing experiments demonstrated that MM cells co-expressing BCL-2 and BCL-X L were resistant to venetoclax but sensitive to navitoclax or the BCL-X L -selective inhibitor A-1155463 (77).…”

Section: Identifying Sensitive Tumor Types and Likely Respondersmentioning

confidence: 99%

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax

Sampath²,

et al. 2017

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Since the discovery of apoptosis as a form of programmed cell death, targeting the apoptosis pathway to induce cancer cell death has been a high priority goal for cancer therapy. After decades of effort, drug discovery scientists have succeeded in generating small-molecule inhibitors of antiapoptotic BCL-2 family proteins. Innovative medicinal chemistry and structure-based drug design, coupled with a strong fundamental understanding of BCL-2 biology, were essential to the development of BH3 mimetics such as the BCL-2-selective inhibitor venetoclax. We review a number of preclinical studies that have deepened our understanding of BCL-2 biology and facilitated the clinical development of venetoclax.

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Section: Identifying Sensitive Tumor Types and Likely Respondersmentioning

confidence: 99%

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax

Sampath²,

et al. 2017

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“…15,16 Similarly, targeting of MCL-1 genetically or pharmacologically in vitro and in vivo induced apoptosis of human MM cell lines. 17,18 Xenograft models that coexpressed BCL-X L or MCL-1 with BCL-2 were resistant to venetoclax. This resistance was mitigated by combining venetoclax with bortezomib, 19 a proteasome inhibitor that can inhibit MCL-1 indirectly via stabilizing the MCL-1-neutralizing protein NOXA.…”

Section: Introductionmentioning

confidence: 99%

Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM

Moreau

Chanan‐Khan

Roberts

et al. 2017

Blood

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Key Points• In relapsed/refractory MM, venetoclax plus bortezomib and dexamethasone appears to be safe and efficacious.• This is a novel therapeutic approach for MM.The antiapoptotic proteins BCL-2 and myeloid cell leukemia sequence 1 (MCL-1) promote multiple myeloma (MM) cell survival. Venetoclax is a selective, orally bioavailable smallmolecule BCL-2 inhibitor; bortezomib can indirectly inhibit MCL-1. In preclinical studies, venetoclax enhanced bortezomib activity, suggesting that cotargeting of BCL-2 and MCL-1 could be an effective treatment strategy in myeloma. This phase 1b trial studied patients with relapsed/refractory MM receiving daily venetoclax (50-1200 mg per designated dose cohort; 800 mg in safety expansion) in combination with bortezomib and dexamethasone. A total of 66 patients were enrolled (54 in the dose-escalation cohorts and 12 in the safety expansion). Patients had received a median of 3 prior therapies (range, 1-13); 26 (39%) were refractory to prior bortezomib and 35 (53%) to lenalidomide; 39 (59%) had prior stem cell transplant. The combination was generally well tolerated, and common adverse events included mild gastrointestinal toxicities ( diarrhea [46%], constipation [41%], and nausea [38%]) and grade 3/4 cytopenias (thrombocytopenia [29%] and anemia [15%]). The overall response rate (ORR) was 67% (44/66); 42% achieved very good partial response or better ( ‡VGPR). Median time to progression and duration of response were 9.5 and 9.7 months, respectively. ORR of 97% and ‡VGPR 73% were seen in patients not refractory to bortezomib who had 1 to 3 prior therapies. Patients with high BCL2 expression had a higher ORR (94% [17/18]) than patients with low BCL2 expression (59% [16/27]). This novel combination of venetoclax with bortezomib and dexamethasone has an acceptable safety profile and promising efficacy in patients with relapsed/refractory MM. This trial was registered at www.clinicaltrials.gov as #NCT01794507. (Blood. 2017;130(22):2392-2400

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“…77 MCL-1 is widely and highly expressed in MM, and it is also an attractive therapeutic target. 78 Recently, a novel MCL-1 inhibitor S63845 was reported to be tolerable and effective in diverse cancer models, 35 making it possible to overcome venetoclax resistance in various types of B-cell lymphoid malignancies.…”

mentioning

confidence: 99%

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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Hierarchy for targeting prosurvival BCL2 family proteins in multiple myeloma: pivotal role of MCL1

Cited by 131 publications

References 49 publications

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax

Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax

Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM

Development of venetoclax for therapy of lymphoid malignancies

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