ArticleOncogene2015
Anti-apoptotic BCL-2 proteins govern cellular outcome following B-RAF(V600E) inhibition and can be targeted to reduce resistance.
Article in Oncogene, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 58 citations in OpenAlex.
- Melanoma: Pathogenesis and Targeted Therapy.MedComm · 2026Review
- Mitochondrial bioenergetics and networks in melanoma: an update.Apoptosis : an international journal on programmed cell death · 2025Review
- Targeting the RAS/RAF/MAPK pathway for cancer therapy: from mechanism to clinical studies.Signal transduction and targeted therapy · 2023Review
- Bcl-2 family inhibitors sensitize human cancer models to therapy.Cell death & disease · 2023Article
- Enhanced Apoptosis and Loss of Cell Viability in Melanoma Cells by Combined Inhibition of ERK and Mcl-1 Is Related to Loss of Mitochondrial Membrane Potential, Caspase Activation and Upregulation of Proapoptotic Bcl-2 Proteins.International journal of molecular sciences · 2023Article
- Lineage-coupled clonal capture identifies clonal evolution mechanisms and vulnerabilities of BRAFCell discovery · 2022Article
- Proteasomal down-regulation of the proapoptotic MST2 pathway contributes to BRAF inhibitor resistance in melanoma.Life science alliance · 2022Article
- Increased apoptotic sensitivity of glioblastoma enables therapeutic targeting by BH3-mimetics.Cell death and differentiation · 2022Article
- Pharmacological inhibition of Ref-1 enhances the therapeutic sensitivity of papillary thyroid carcinoma to vemurafenib.Cell death & disease · 2022Article
- Bcl-xL: A Focus on Melanoma Pathobiology.International journal of molecular sciences · 2021Review
- BCL2L10 Is Overexpressed in Melanoma Downstream of STAT3 and Promotes Cisplatin and ABT-737 Resistance.Cancers · 2020Article
- Inhibition of Anti-Apoptotic Bcl-2 Proteins in Preclinical and Clinical Studies: Current Overview in Cancer.Cells · 2020Review
- Non-Apoptotic Cell Death Signaling Pathways in Melanoma.International journal of molecular sciences · 2020Review
- Inhibition of BCL2 Family Members Increases the Efficacy of Copper Chelation in BRAFCancer research · 2020Article
- Destabilization of NOXA mRNA as a common resistance mechanism to targeted therapies.Nature communications · 2019Article
- Targeting melanoma's MCL1 bias unleashes the apoptotic potential of BRAF and ERK1/2 pathway inhibitors.Nature communications · 2019Article
- Melatonin Enhances Autophagy and Reduces Apoptosis to Promote Locomotor Recovery in Spinal Cord Injury via the PI3K/AKT/mTOR Signaling Pathway.Neurochemical research · 2019Article
- Melatonin Prevents Oxidative Stress-Induced Mitochondrial Dysfunction and Apoptosis in High Glucose-Treated Schwann Cells via Upregulation of Bcl2, NF-κB, mTOR, Wnt Signalling Pathways.Antioxidants (Basel, Switzerland) · 2019Article
- BCL-XL and MCL-1 are the key BCL-2 family proteins in melanoma cell survival.Cell death & disease · 2019Article
- Article
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
In theory, pharmacological inhibition of oncogenic signaling is an effective strategy to halt cellular proliferation, induce apoptosis and eliminate cancer cells. In practice, drugs (for example, PLX-4032) that inhibit oncogenes like B-RAFV600E provide relatively short-term success in patients, owing to a combination of incomplete cellular responses and the development of resistance. To define the relationship between PLX-4032-induced responses and resistance, we interrogated the contributions of anti-apoptotic BCL-2 proteins in determining the fate of B-RAFV600E-inhibited melanoma cells. Although PLX-4032 eliminated B-RAFV600E signaling leading to marked cell cycle arrest, only a fraction of cells eventually underwent apoptosis. These data proposed two hypotheses regarding B-RAFV600E inhibition: (1) only a few cells generate a pro-apoptotic signal, or (2) all the cells generate a pro-apoptotic signal but the majority silences this pathway to ensure survival. Indeed, the latter hypothesis is supported by our observations as the addition of ABT-737, an inhibitor to anti-apoptotic BCL-2 proteins, revealed massive apoptosis following PLX-4032 exposure. B-RAFV600E inhibition alone sensitized cells to the mitochondrial pathway of apoptosis characterized by the rapid accumulation of BIM on the outer mitochondrial membrane, which could be functionally revealed by ABT-737 to promote apoptosis and loss of clonogenic survival. Furthermore, PLX-4032-resistant cells demonstrated collateral resistance to conventional chemotherapy, yet could be re-sensitized to PLX-4032 by BCL-2 family inhibition in vivo and conventional chemotherapies in vitro. Our data suggest that inhibiting anti-apoptotic BCL-2 proteins will enhance primary responses to PLX-4032, along with reducing the development of resistance to both targeted and conventional therapies.
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