ArticleMolecular cancer research : MCR2012
Phosphoinositide 3-kinase/AKT/mTORC1/2 signaling determines sensitivity of Burkitt's lymphoma cells to BH3 mimetics.
Article in Molecular cancer research : MCR, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 45 citations in OpenAlex.
- Potent combination benefit of the AKT inhibitor capivasertib and the BCL-2 inhibitor venetoclax in diffuse large B cell lymphoma.Leukemia · 2024Article
- C-Myc inhibition intensified the anti-leukemic properties of Imatinib in chronic myeloid leukemia cells.Molecular biology reports · 2023Article
- The BCL-2 family protein inhibitor ABT-737 as an additional tool for the treatment of EBV-associated post-transplant lymphoproliferative disorders.Molecular oncology · 2020Article
- NOTCH1 Represses MCL-1 Levels in GSI-resistant T-ALL, Making them Susceptible to ABT-263.Clinical cancer research : an official journal of the American Association for Cancer Research · 2019Article
- Biological Aspects of mTOR in Leukemia.International journal of molecular sciences · 2018Review
- Article
- Loss of PIM2 enhances the anti-proliferative effect of the pan-PIM kinase inhibitor AZD1208 in non-Hodgkin lymphomas.Molecular cancer · 2015Article
- MCL-1-independent mechanisms of synergy between dual PI3K/mTOR and BCL-2 inhibition in diffuse large B cell lymphoma.Oncotarget · 2015Article
- Co-targeting of Bcl-2 and mTOR pathway triggers synergistic apoptosis in BH3 mimetics resistant acute lymphoblastic leukemia.Oncotarget · 2015Article
- HGUE-C-1 is an atypical and novel colon carcinoma cell line.BMC cancer · 2015Article
- β-TrCP1 degradation is a novel action mechanism of PI3K/mTOR inhibitors in triple-negative breast cancer cells.Experimental & molecular medicine · 2015Article
- Co-administration of ABT-737 and SAHA induces apoptosis, mediated by Noxa upregulation, Bax activation and mitochondrial dysfunction in PTEN-intact malignant human glioma cell lines.Journal of neuro-oncology · 2014Article
- B-cell activating factor-receptor specific activation of tumor necrosis factor receptor associated factor 6 and the phosphatidyl inositol 3-kinase pathway in lymphoma B cells.Leukemia & lymphoma · 2014Article
- Inhibition of phosphatidylinositol 3-kinase/AKT signaling by NVP-BKM120 promotes ABT-737-induced toxicity in a caspase-dependent manner through mitochondrial dysfunction and DNA damage response in established and primary cultured glioblastoma cells.The Journal of pharmacology and experimental therapeutics · 2014Article
- Developments in Burkitt's lymphoma: novel cooperations in oncogenic MYC signaling.Cancer management and research · 2014Review
- PI3K inhibitor GDC-0941 enhances apoptotic effects of BH-3 mimetic ABT-737 in AML cells in the hypoxic bone marrow microenvironment.Journal of molecular medicine (Berlin, Germany) · 2013Article
- Clinical development of phosphatidylinositol 3-kinase inhibitors for non-Hodgkin lymphoma.Biomarker research · 2013Article
- Article
- That which does not kill me makes me stronger; combining ERK1/2 pathway inhibitors and BH3 mimetics to kill tumour cells and prevent acquired resistance.British journal of pharmacology · 2013Review
- Blockade of PI3K/AKT pathway enhances sensitivity of Raji cells to chemotherapy through down-regulation of HSP70.Cancer cell international · 2013Article
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
Abstract
Burkitt's lymphoma (BL), driven by translocation and overexpression of the c-MYC gene, is an aggressive, highly proliferative lymphoma, and novel therapeutic strategies are required to overcome drug resistance following conventional treatments. The importance of the prosurvival BCL-2 family member BCL-X(L) in BL cell survival suggests that antagonistic BH3-mimetic compounds may have therapeutic potential. Here, we show that treatment of BL cell lines with ABT-737 induces caspase-3/7 activation and apoptosis with varying potency. Using selective inhibitors, we identify phosphoinositide 3-kinase (PI3K) as a proproliferative/survival pathway in BL cells and investigate the potential of combined pharmacologic inhibition of both the BCL-2 family and PI3K signaling pathway. PI3K/AKT inhibition and ABT-737 treatment induced synergistic caspase activation, augmented BL cell apoptosis, and rendered chemoresistant cells sensitive. Targeting mTORC1/2 with PP242 was also effective, either as a monotherapy or, more generally, in combination with ABT-737. The combined use of a dual specificity PI3K/mTOR inhibitor (PI 103) with ABT-737 proved highly efficacious. PI 103 treatment of BL cells was associated with an increase in BIM/MCL-1 expression ratios and loss of c-MYC expression. Furthermore, blocking c-MYC function using the inhibitor 10058-F4 also induced apoptosis synergistically with ABT-737, suggesting that maintenance of expression of BCL-2 family members and/or c-MYC by the PI3K/AKT/mTOR pathway could contribute to BL cell survival and resistance to ABT-737. The combined use of BH3 mimetics and selective mTORC1/2 inhibitors may therefore be a useful novel therapeutic approach for the treatment of B-cell malignancy, including chemoresistant lymphomas.
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