ArticleTranslational oncology2022
Co-targeting MCL-1 and ERK1/2 kinase induces mitochondrial apoptosis in rhabdomyosarcoma cells.
Article in Translational oncology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 11 citations in OpenAlex.
- Molecular Targets in Alveolar Rhabdomyosarcoma: A Narrative Review of Progress and Pitfalls.International journal of molecular sciences · 2025Review
- Disrupting resistance: novel therapeutic approaches to combat multidrug resistance in fusion-negative rhabdomyosarcoma.Cancer drug resistance (Alhambra, Calif.) · 2025Review
- Proteomic profiling reveals CEACAM6 function in driving gallbladder cancer aggressiveness through integrin receptor, PRKCD and AKT/ERK signaling.Cell death & disease · 2024Article
- Effective Targeting of Melanoma Cells by Combination of Mcl-1 and Bcl-2/Bcl-xInternational journal of molecular sciences · 2024Article
- Potential biomarkers for MCL1 inhibitor sensitivity.Cell signaling · 2024Article
- Article
- Synergistic Action of MCL-1 Inhibitor with BCL-2/BCL-XL or MAPK Pathway Inhibitors Enhances Acute Myeloid Leukemia Cell Apoptosis and Differentiation.International journal of molecular sciences · 2023Article
- The first-in-class ERK inhibitor ulixertinib shows promising activity in mitogen-activated protein kinase (MAPK)-driven pediatric low-grade glioma models.Neuro-oncology · 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
- Targeting MCL-1 protein to treat cancer: opportunities and challenges.Frontiers in oncology · 2023Review
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The RAS/MEK/ERK genetic axis is commonly altered in rhabdomyosarcoma (RMS), indicating high activity of downstream effector ERK1/2 kinase. Previously, we have demonstrated that inhibition of the RAS/MEK/ERK signaling pathway in RMS is insufficient to induce cell death due to residual pro-survival MCL-1 activity. Here, we show that the combination of ERK1/2 inhibitor Ulixertinib and MCL-1 inhibitor S63845 is highly synergistic and induces apoptotic cell death in RMS in vitro and in vivo. Importantly, Ulixertinib/S63845 co-treatment suppresses long-term survival of RMS cells, induces rapid caspase activation and caspase-dependent apoptosis. Mechanistically, Ulixertinib-mediated upregulation of BIM and BMF in combination with MCL-1 inhibition by S63845 shifts the balance of BCL-2 proteins towards a pro-apoptotic state resulting in apoptosis induction. A genetic silencing approach reveals that BIM, BMF, BAK and BAX are all required for Ulixertinib/S63845-induced apoptosis. Overexpression of BCL-2 rescues cell death triggered by Ulixertinib/S63845 co-treatment, confirming that combined inhibition of ERK1/2 and MCL-1 effectively induces cell death of RMS cells via the intrinsic mitochondrial apoptotic pathway. Thus, this study is the first to demonstrate the cytotoxic potency of co-inhibition of ERK1/2 and MCL-1 for RMS treatment.
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