BET Inhibitors Synergize with Carfilzomib to Induce Cell Death in Cancer Cells via Impairing Nrf1 Transcriptional Activity and Exacerbating the Unfolded Protein Response

Vangala, Janakiram R.; Potluri, Ajay; Radhakrishnan, Senthil K.

doi:10.3390/biom10040501

Cited by 20 publications

(21 citation statements)

References 49 publications

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“…Using high-throughput combination screens, we identified several classes of drugs synergizing with BETi in an unbiased manner. Some of these candidates, such as BCL2 inhibitors and HDAC inhibitors, have been shown previously to potentiate the antitumor effects of BETi in SCLC (7,10), while several others, such as inhibitors of cyclin-dependent kinases and carfilzomib, were reported to synergize with BETi in other tumor types (40,41). These earlier studies indirectly validate our results, suggesting shared vulnerabilities between various tumor types.…”

Section: Discussionsupporting

confidence: 89%

mTOR Inhibition Overcomes RSK3-mediated Resistance to BET Inhibitors in Small Cell Lung Cancer

Kumari

Gesumaria

Liu

et al. 2021

Preprint

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PurposeSCLC is a recalcitrant malignancy with limited treatment options. BET inhibitors have shown promising preclinical activity in SCLC, but their broad sensitivity spectrum limits their clinical prospects in this malignancy. Drug combination could be a solution.Experimental designWe performed high-throughput drug combination screens in SCLC cell lines to identify potential therapeutics synergizing with BET inhibitors. Validation was performed in SCLC cell lines and patient-derived xenograft models. Genome-wide RNA sequencing of xenograft tumors was performed to determine the mechanism underlying the synergy of the drug combination.ResultsInhibitors of the PI-3K-AKT-mTOR pathway were the top candidates from the screens. Among the therapeutics targeting this pathway, mTOR inhibitors showed the highest degree of synergy with BET inhibitors in vitro. Furthermore, the combination of these two classes of drugs showed superior antitumor efficacy and tolerability in vivo. Using both in vitro and in vivo SCLC models, we demonstrate that BET inhibitors activate the intrinsic apoptotic cascade, and mTOR inhibitors further enhance these apoptotic effects. Mechanistically, BET inhibitors activate the TSC2-mTOR-p70S6K1 signaling cascade by upregulating RSK3, an upstream kinase of TSC2. Activation of p70S6K1 leads to BAD phosphorylation and cell survival. mTOR inhibition blocks this survival signaling cascade and potentiates the antitumor effects of BET inhibitors.ConclusionsOur results demonstrate that RSK3 upregulation is a novel resistance mechanism of BET inhibitors in SCLC, and mTOR inhibition can overcome this resistance and enhance apoptosis. These findings provide a rationale to evaluate the combination of mTOR and BET inhibitors in patients with SCLC.

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Section: Discussionsupporting

confidence: 89%

mTOR Inhibition Overcomes RSK3-mediated Resistance to BET Inhibitors in Small Cell Lung Cancer

Kumari

Gesumaria

Liu

et al. 2021

Preprint

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“…The authors speculated that the JQ1/carfilzomib combination enhances ER stress leading to the activation of CHOP/EBPα, increased BIM transcription, and consequent apoptosis [ 124 ] ( Figure 5 ). Accordingly, a recent study showed that BET inhibitors synergize with carfilzomib in multiple solid tumor cell lines [ 24 ]. In addition, Siegel et al described that the selective BRD4 inhibitor CPI203 showed synergy with bortezomib in resistant cell lines as well as in a primary sample from RRMM patient.…”

Section: Emerging Proteasome Inhibitors Drug Combinations Targetinmentioning

confidence: 99%

“…To this end, the use of combinatorial treatments might allow lowering the dose of inhibitors and therefore, minimize their side-effects. In addition, although PIs failed as single agents for the treatment of solid tumors in clinics [ 16 ], there are accumulating pieces of evidence that the combination of proteasomal inhibition with various drugs could improve the outcome of a wide range of malignant diseases [ 22 , 23 , 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

The Landscape of Signaling Pathways and Proteasome Inhibitors Combinations in Multiple Myeloma

Paradžik

Bandini

Mereu

et al. 2021

Cancers

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Multiple myeloma is a malignancy of terminally differentiated plasma cells, characterized by an extreme genetic heterogeneity that poses great challenges for its successful treatment. Due to antibody overproduction, MM cells depend on the precise regulation of the protein degradation systems. Despite the success of PIs in MM treatment, resistance and adverse toxic effects such as peripheral neuropathy and cardiotoxicity could arise. To this end, the use of rational combinatorial treatments might allow lowering the dose of inhibitors and therefore, minimize their side-effects. Even though the suppression of different cellular pathways in combination with proteasome inhibitors have shown remarkable anti-myeloma activities in preclinical models, many of these promising combinations often failed in clinical trials. Substantial progress has been made by the simultaneous targeting of proteasome and different aspects of MM-associated immune dysfunctions. Moreover, targeting deranged metabolic hubs could represent a new avenue to identify effective therapeutic combinations with PIs. Finally, epigenetic drugs targeting either DNA methylation, histone modifiers/readers, or chromatin remodelers are showing pleiotropic anti-myeloma effects alone and in combination with PIs. We envisage that the positive outcome of patients will probably depend on the availability of more effective drug combinations and treatment of early MM stages. Therefore, the identification of sensitive targets and aberrant signaling pathways is instrumental for the development of new personalized therapies for MM patients.

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“…Beyond that, in virtue of BET inhibitors, the ability of transcription factor Nrf1 to induce proteasal genes to proteasal inhibition is weakened, hindering the rebound reaction of proteasal activity, which is the key pathway for cells to address protein toxic stress. BET inhibitors have the potential to combine with carfilzomib to treat solid tumors (29).…”

Section: New Mechanismsmentioning

confidence: 99%

Recent Research Progress of Chiral Small Molecular Antitumor-Targeted Drugs Approved by the FDA From 2011 to 2019

Chu

Yang

2021

Front. Oncol.

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Chiral drugs usually contain chiral centers, which are present as single enantiomers or racemates. Compared with achiral drugs, they have significant advantages in safety and efficacy with high stereoselectivity. Of these drugs, chirality not only exerts influence on the solubility and pharmacokinetic characteristics but also has specific mechanistic characteristics on their targets. We noted that small molecules with unique chiral properties have emerged as novel components of antitumor drugs approved by the FDA in decade. Since approved, these drugs have been continuously explored for new indications, new mechanisms, and novel combinations. In this mini review, recent research progress of twenty-two FDA-approved chiral small molecular-targeted antitumor drugs from 2011 to 2019 is summarized with highlighting the potential and advantages of their applications. We believe that these updated achievements may provide theoretical foundation and stimulate research interests for optimizing drug efficacy, expanding clinical application, overcoming drug resistance, and advancing safety in future clinical administrations of these chiral targeted drugs.

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BET Inhibitors Synergize with Carfilzomib to Induce Cell Death in Cancer Cells via Impairing Nrf1 Transcriptional Activity and Exacerbating the Unfolded Protein Response

Cited by 20 publications

References 49 publications

mTOR Inhibition Overcomes RSK3-mediated Resistance to BET Inhibitors in Small Cell Lung Cancer

mTOR Inhibition Overcomes RSK3-mediated Resistance to BET Inhibitors in Small Cell Lung Cancer

The Landscape of Signaling Pathways and Proteasome Inhibitors Combinations in Multiple Myeloma

Recent Research Progress of Chiral Small Molecular Antitumor-Targeted Drugs Approved by the FDA From 2011 to 2019

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