Synthetic Lethality of Combined Bcl-2 Inhibition and p53 Activation in AML: Mechanisms and Superior Antileukemic Efficacy

Pan, Rongqing; Ruvolo, Vivian; Mu, Hong; Leverson, Joel D.; Nichols, Gwen; Reed, John C.; Konopleva, Marina; Andreeff, Michael

doi:10.1016/j.ccell.2017.11.003

Cited by 229 publications

(236 citation statements)

References 37 publications

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“…Therefore, TP53 activation may overcome AML resistance to BCL‐2 inhibition, and indeed, combined TP53 activation and BCL‐2 inhibition show synergistic efficacy in AML . This mechanistic study provides strong support for an ongoing clinical trial combining these two classes of drugs in human AML (clinical trial NCT02670044).…”

Section: Targeting the Tp53 Pathwaymentioning

confidence: 59%

“…One example is the combination of MDM2 inhibitors and BCL2 inhibitors in AML. 147,148 It is well known that in addition to TP53 inactivation, cancer cells escape apoptosis by activation of anti-apoptotic BCL-2 family members (eg, BCL-xL, BCL-2, and MCL-1). 149 These antiapoptotic proteins bind proapoptotic proteins (eg, BAX and BAK), thus preventing apoptosis induction.…”

Section: Which Disrupts the Interaction Between Tp53 And Both Mdm2mentioning

confidence: 99%

“…150 The BCL-2 inhibitor Venetoclax/ABT-199 is a BH3 mimetic that antagonizes these protein-protein interactions, freeing proapoptotic proteins BAX and BAK and effectively inducing mitochondrial damage and cell death. 148,151,152 However, treatment-resistant AML with a heightened apoptotic threshold, such as high levels of the antiapoptotic protein MCL-1, may be insensitive to Venetoclax as a monotherapy. 148,153,154 It was recently demonstrated that TP53 regulates MCL-1 degradation by RAS/RAF/MEK/ERK signaling.…”

Section: Which Disrupts the Interaction Between Tp53 And Both Mdm2mentioning

confidence: 99%

“…148,151,152 However, treatment-resistant AML with a heightened apoptotic threshold, such as high levels of the antiapoptotic protein MCL-1, may be insensitive to Venetoclax as a monotherapy. 148,153,154 It was recently demonstrated that TP53 regulates MCL-1 degradation by RAS/RAF/MEK/ERK signaling. In detail, TP53 activation reduces phosphorylated MEK and ERK, in turn attenuating MCL-1 phosphorylation on Thr163, a modification that promotes its stability.…”

Section: Which Disrupts the Interaction Between Tp53 And Both Mdm2mentioning

confidence: 99%

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The role of TP53 in acute myeloid leukemia: Challenges and opportunities

Barbosa

Adams

et al. 2019

Genes Chromosomes & Cancer

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The tumor suppressor gene TP53 is one of the most frequently mutated genes in human cancer. The central role of the TP53 protein in several fundamental processes such as cancer, aging, senescence, and DNA repair has ensured enormous attention. However, the role of TP53 in acute myeloid leukemia (AML) is enigmatic. Unlike many other human cancers, a vast majority of AMLs display no genomic TP53 alterations. There is now growing appreciation of the fact that the unaltered TP53 status of tumor cells can be exploited therapeutically. As most AMLs have an intact TP53 gene, its physiological tumor‐suppressive roles could be harnessed. Therefore, the use of pharmacological activators of the TP53 pathway may provide clinical benefit in AML. Conversely, even though the frequency of TP53 mutations in AML is substantially lower than in other human cancers, TP53 mutations are associated with chemoresistance and high risk of relapse. In patients with TP53 mutations, these alterations may lead to novel, selective vulnerabilities, creating opportunities for therapeutic targeting of TP53 mutant AML. The mutational status of TP53 therefore poses challenges and opportunities in terms of advancing effective treatment strategies in AML. An increasing armamentarium of small‐molecule activators of the TP53 pathway, and a growing understanding of molecular pathways triggered by mutant TP53 have accelerated efforts aimed at targeting TP53 function in AML. In combination with standard AML chemotherapy or emerging targeted therapies, pharmacological targeting of the TP53 pathway may provide therapeutic benefit in AML.

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Section: Targeting the Tp53 Pathwaymentioning

confidence: 59%

Section: Which Disrupts the Interaction Between Tp53 And Both Mdm2mentioning

confidence: 99%

Section: Which Disrupts the Interaction Between Tp53 And Both Mdm2mentioning

confidence: 99%

Section: Which Disrupts the Interaction Between Tp53 And Both Mdm2mentioning

confidence: 99%

See 2 more Smart Citations

The role of TP53 in acute myeloid leukemia: Challenges and opportunities

Barbosa

Adams

et al. 2019

Genes Chromosomes & Cancer

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“…Combined inhibition of BCL-2 and the NEDD8 activating enzyme (NAE), which triggers increased expression of NOXA and MCL-1 antagonism, has also demonstrated synergistic activity in AML models (110). Recently, the combination of the selective MDM2 antagonist idasanutlin and venetoclax demonstrated synergistic anti-tumor activity in p53 wild-type AML cell lines, and led to superior efficacy and survival relative to either agent on its own in subcutaneous and systemic AML models (111, 112). These findings prompted the initiation of a Phase 1b study (Table 1).…”

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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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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Synthetic Lethality of Combined Bcl-2 Inhibition and p53 Activation in AML: Mechanisms and Superior Antileukemic Efficacy

Cited by 229 publications

References 37 publications

The role of TP53 in acute myeloid leukemia: Challenges and opportunities

The role of TP53 in acute myeloid leukemia: Challenges and opportunities

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

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

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