Combined venetoclax and alvocidib in acute myeloid leukemia

Bogenberger, James M; Whatcott, Clifford J.; Hansen, Nanna; Delman, Devora; Shi, Chao; Kim, Wontak; Haws, Hillary; Soh, Katherine K.; Lee, Ye Sol; Peterson, Peter; Siddiqui‐Jain, Adam; Weitman, Steven; Stewart, Keith; Bearss, David J.; Mesa, Ruben A.; Warner, Steven L.; Tibes, Raoul

doi:10.18632/oncotarget.22284

Cited by 68 publications

(61 citation statements)

References 60 publications

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“…Down-regulation of transcription by CDK9 inhibition broadly and preferentially affects proteins with a short half-life, such as MCL-1 (161)(162)(163). Consistent with this evidence, alvocidib treatment has been shown to decrease MCL-1 levels in AML and chronic lymphocytic leukemia cells (Figure 2C) (30,162,164). Alvocidib induces apoptosis in many tumor cell lines, including those derived from lymphoma, MM, and AML (8).…”

Section: Cdk7 and Cdk9supporting

confidence: 55%

“…An alternative approach is to indirectly inhibit the antiapoptotic function of MCL-1. Indirect targeting of MCL-1 by inhibition of specific CDK isoforms that regulate transcription, particularly CDK9 or CDK7, has shown promising preclinical and clinical outcomes (8,29,30).…”

Section: Bcl-2 Family Of Proteins Including Mcl-1 In Aml Pathogenesismentioning

confidence: 99%

“…With regard to BCL-2 family inhibition, combination strategies including CDK9 inhibitors aim to overcome MCL-1-dependent drug resistance via transcriptional silencing of MCL-1. CDK9 inhibitors can also overcome intrinsic apoptotic resistance via induction of pro-apoptotic BH3-only proteins, such as BIM, possibly occurring through transcriptional downregulation of miRNAs that negatively regulate these proapoptotic BH3-only proteins (30,161,162,179). Considering these premises, potential synergistic partners for CDK9 inhibitors include small molecules known to inhibit BCL-2 family proteins, such as navitoclax (ABT-263; AbbVie, Inc., North Chicago, IL, USA) and venetoclax (30,62,172).…”

Section: Combination Therapy Utilizing Cdk9 Inhibitionmentioning

confidence: 99%

“…Recent functional screens using CRISPR/Cas9 approaches highlight the central importance of mitochondrial function/architecture in resistance to BCL-2 inhibitor venetoclax (27,28). Other BCL-2 family protein members may also play a role in AML patients refractory/resistant to BCL-2 inhibition, particularly MCL-1, which is an antiapoptotic multidomain protein regulated by distinct cyclin-dependent kinases (CDKs) in both apoptotic and cell-cycling pathways (8,(29)(30)(31).…”

Section: Introductionmentioning

confidence: 99%

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Transcriptional Silencing of MCL-1 Through Cyclin-Dependent Kinase Inhibition in Acute Myeloid Leukemia

Tibes

Bogenberger

2019

Front. Oncol.

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Acute myeloid leukemia (AML) is the most common adult acute leukemia. Survival remains poor, despite decades of scientific advances. Cytotoxic induction chemotherapy regimens are standard-of-care for most patients. Many investigations have highlighted the genomic heterogeneity of AML, and several new targeted therapeutic options have recently been approved. Additional novel therapies are showing promising clinical results and may rapidly transform the therapeutic landscape of AML. Despite the emerging clinical success of B-cell lymphoma (BCL)-2 targeting in AML and a large body of preclinical data supporting myeloid leukemia cell (MCL)-1 as an attractive therapeutic target for AML, MCL-1 targeting remains relatively unexplored, although novel MCL-1 inhibitors are under clinical investigation. Inhibitors of cyclin-dependent kinases (CDKs) involved in the regulation of transcription, CDK9 in particular, are being investigated in AML as a strategy to target MCL-1 indirectly. In this article, we review the basis for CDK inhibition in oncology with a focus on relevant preclinical mechanism-of-action studies of CDK9 inhibitors in the context of their therapeutic potential specifically in AML.

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Section: Cdk7 and Cdk9supporting

confidence: 55%

Section: Bcl-2 Family Of Proteins Including Mcl-1 In Aml Pathogenesismentioning

confidence: 99%

Section: Combination Therapy Utilizing Cdk9 Inhibitionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Transcriptional Silencing of MCL-1 Through Cyclin-Dependent Kinase Inhibition in Acute Myeloid Leukemia

Tibes

Bogenberger

2019

Front. Oncol.

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“…Bogenberger et al showed that alvocidib (also known as flavopiridol), a potent CDK9 inhibitor, downregulated MCL-1 expression and increased BIM expression, inducing synergistic apoptosis when combined with venetoclax in venetoclax-resistant AML cell lines (such as OCI-AML3), patient-derived samples, and a mouse xenograft model of OCI-AML3. 40 Knorr et al demonstrated that MLN4924 (also known as pevonedistat), an inhibitor of the Nedd8 activating enzyme, inactivated E3 cullin ring ligases, causing accumulation of the cullin ring ligase substrate c-Myc, which transactivated the PMAIP1 gene encoding NOXA, inducing upregulation of NOXA and subsequent MCL-1 inhibition. This led to synergistic apoptosis when combined with venetoclax both in cell lines and primary patient samples.…”

Section: Combination Strategies To Boost Venetoclax Activity and Overmentioning

confidence: 99%

Venetoclax for AML: changing the treatment paradigm

Pollyea

Amaya

Strati³

et al. 2019

Blood Advances

134

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Venetoclax is a specific B-cell lymphoma-2 (BCL-2) inhibitor that can restore activation of apoptosis in malignancies, the survival of which depends on dysregulation of this pathway.Preclinical data, using various model systems including cell lines and patient samples, suggested targeting BCL-2 could be a successful therapeutic strategy in patients with acute myeloid leukemia (AML). As predicted by this work, the use of venetoclax in the clinical setting has resulted in promising outcomes for patients with this disease. Although venetoclax showed limited activity as a single agent in the relapsed disease setting, recent studies have shown that when combined with a backbone therapy of a hypomethylating agent or low-dose cytarabine, high response rates with encouraging remission durations for older patients with newly diagnosed AML who were not candidates for intensive induction chemotherapy were observed. Furthermore, venetoclax-based therapies allowed for rapid responses and were able to effectively target the leukemia stem cell population. Here we review the preclinical data that supported the development of venetoclax in AML, as well as the results of the promising clinical trials. Preclinical development The intrinsic apoptotic pathwayThe B-cell lymphoma-2 (BCL-2) family includes multiple proteins sharing BCL-2-like homology domains 1-4 (BH1-BH4), each playing a specific role in the intrinsic apoptotic pathway. The BCL-2 family proteins' roles can be divided into 4 main functions: suppressors (BCL-2, BCL-XL, BCL-W, BCL2-A1, and MCL-1), activators (BIM and PUMA), effectors (BAX and BAK), and sensitizers (NOXA). 8,9 Suppressors inhibit the activity of activators and effectors, preventing apoptosis, whereas sensitizers inhibit suppressors, releasing the brake on activators and effectors. The latter oligomerize, creating

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Abivertinib synergistically strengthens the anti‐leukemia activity of venetoclax in acute myeloid leukemia in a BTK‐dependent manner

Huang

Zhang

et al. 2020

Molecular Oncology

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B-cell lymphoma 2 (BCL-2), a crucial member of the anti-apoptotic BCL-2 family, is frequently dysregulated in cancer and plays an important role in acute myeloid leukemia (AML). Venetoclax is a highly selective BCL-2 inhibitor that has been approved by the FDA for treating elderly AML patients. However, the emergence of resistance after long-term treatment emphasizes the need for a deeper understanding of the potential mechanisms of resistance and effective rescue methods. By using RNA-seq analysis in two human AML cohorts made up of three patients with complete remission and three patients without remission after venetoclax treatment, we identified that upregulation of BTK enabled AML blast resistance to venetoclax. Interestingly, we found that abivertinib, an oral BTK inhibitor, could synergize with venetoclax to inhibit the proliferation of primary AML cells and cell lines. It is worth noting that the combination of the two effectively enhanced the sensitivity of two AML patients (AML#3 and AML#12) to venetoclax. In this study, we demonstrated that combined use of the two drugs can synergistically inhibit the colony-forming capacity of AML cells, arrest the AML cell cycle in the G0/G1 phase, and inhibit the BCL-2 anti-apoptotic family protein, activating the caspase family to induce apoptosis. Mechanistically, knockdown of BTK in AML cell lines impaired the synergistic effect of the two drugs. In vivo study showed similar results as those seen in vitro. Abivertinib in combination with venetoclax could significantly prolong the survival time and reduce the tumor burden of MV4-11-NSG mice compared with those of control and single-agent groups. Our in vitro and in vivo studies have shown that the combination of abivertinib and venetoclax may benefit AML patients, especially in patients resistant to venetoclax or those that relapse. New clinical trials will be planned.

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Combined venetoclax and alvocidib in acute myeloid leukemia

Cited by 68 publications

References 60 publications

Transcriptional Silencing of MCL-1 Through Cyclin-Dependent Kinase Inhibition in Acute Myeloid Leukemia

Transcriptional Silencing of MCL-1 Through Cyclin-Dependent Kinase Inhibition in Acute Myeloid Leukemia

Venetoclax for AML: changing the treatment paradigm

Abivertinib synergistically strengthens the anti‐leukemia activity of venetoclax in acute myeloid leukemia in a BTK‐dependent manner

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