ArticleOncotarget2015
MCL-1-independent mechanisms of synergy between dual PI3K/mTOR and BCL-2 inhibition in diffuse large B cell lymphoma.
Article in Oncotarget, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
20 citing papers in PubMed, 25 citations in OpenAlex.
- Article
- Potent combination benefit of the AKT inhibitor capivasertib and the BCL-2 inhibitor venetoclax in diffuse large B cell lymphoma.Leukemia · 2024Article
- Potent combination benefit of the AKT inhibitor capivasertib and the BCL-2 inhibitor venetoclax in diffuse large B cell lymphoma.Leukemia · 2024Article
- Targeting MCL-1 protein to treat cancer: opportunities and challenges.Frontiers in oncology · 2023Review
- A Phase II Study to Assess the Safety and Efficacy of the Dual mTORC1/2 and PI3K Inhibitor Bimiralisib (PQR309) in Relapsed, Refractory Lymphoma.HemaSphere · 2021Article
- Copanlisib synergizes with conventional and targeted agents including venetoclax in B- and T-cell lymphoma models.Blood advances · 2020Article
- Is There a Role for Dual PI3K/mTOR Inhibitors for Patients Affected with Lymphoma?International journal of molecular sciences · 2020Review
- Statins enhance efficacy of venetoclax in blood cancers.Science translational medicine · 2018Article
- Article
- Predicting effective pro-apoptotic anti-leukaemic drug combinations using co-operative dynamic BH3 profiling.PloS one · 2018Article
- MCL-1 inhibition in cancer treatment.OncoTargets and therapy · 2018Review
- Found in Translation: How Preclinical Research Is Guiding the Clinical Development of the BCL2-Selective Inhibitor Venetoclax.Cancer discovery · 2017Review
- Targeting BET proteins improves the therapeutic efficacy of BCL-2 inhibition in T-cell acute lymphoblastic leukemia.Leukemia · 2017Article
- Rituximab-Based Therapy in Newly Diagnosed Diffuse Large B-Cell Lymphoma Patients: Individualized Risk-Adapted Therapy Approach Using Molecular Subtypes.Journal of hematology · 2017Review
- The landscape of new drugs in lymphoma.Nature reviews. Clinical oncology · 2017Review
- Bruton tyrosine kinase inhibitor ONO/GS-4059: from bench to bedside.Oncotarget · 2017Review
- Development of venetoclax for therapy of lymphoid malignancies.Drug design, development and therapy · 2017Review
- Targeting mTOR for the treatment of B cell malignancies.British journal of clinical pharmacology · 2016Review
- Article
- Low dose of lenalidmide and PI3K/mTOR inhibitor trigger synergistic cytoxicity in activated B cell-like subtype of diffuse large B cell lymphoma.Journal of experimental & clinical cancer research : CR · 2016Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The PI3K/AKT/mTOR axis promotes survival and is a frequently mutated pathway in cancer. Yet, inhibitors targeting this pathway are insufficient to induce cancer cell death as single agents in some contexts, including diffuse large B cell lymphoma (DLBCL). In these situations, combinations with inhibitors targeting BCL-2 survival proteins (ABT-199 and ABT-263) may hold potential. Indeed, studies have demonstrated marked synergy in contexts where PI3K/mTOR inhibitors suppress expression of the pro-survival protein, MCL-1. In this study, we use BH3 profiling to confirm that BCL-2 and BCL-XL support survival following PI3K pathway inhibition, and that the dual PI3K/mTOR inhibitor BEZ235 strongly synergizes with BCL-2 antagonists in DLBCL. However, we identify an alternative mechanism of synergy between PI3K/mTOR and BCL-2 inhibitors, independent of MCL-1 down-regulation. Instead, we show that suppression of AKT activation by BEZ235 can induce the mitochondrial accumulation of pro-apoptotic BAD and BIM, and that expression of a constitutively active form of AKT prevents sensitization to BCL-2 antagonism. Thus, our work identifies an additional mechanism of synergy between PI3K pathway inhibitors and BCL-2 antagonists that strengthens the rationale for testing this combination in DLBCL.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.