ArticleJournal of hepatology2018
Fibroblast growth factor receptor inhibition induces loss of matrix MCL1 and necrosis in cholangiocarcinoma.
Article in Journal of hepatology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers, 2 of them syntheses that pooled it.
What it found
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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
16 citing papers in PubMed, 2 syntheses or guidelines pooled it, 21 citations in OpenAlex.
- Criteria for preclinical models of cholangiocarcinoma: scientific and medical relevance.Nature reviews. Gastroenterology & hepatology · 2023Guideline
- Molecular Targets and Signaling Pathways in Cholangiocarcinoma: A Systematic Review.Asian Pacific journal of cancer prevention : APJCP · 2023Pooled it
- Discovery of a covalent FGFR2-selective inhibitor overcoming clinically-acquired resistance mutations.Nature communications · 2026Article
- MCL-1 as a tumor microenvironment-linked survival node in cholangiocarcinoma.Frontiers in oncology · 2026Article
- Harnessing the FGFR2/NF2/YAP signaling-dependent necroptosis to develop an FGFR2/IL-8 dual blockade therapeutic strategy.Nature communications · 2025Article
- Sorcin Inhibits Mitochondrial Apoptosis by Interacting with STAT3 via NF-κB Pathway.International journal of molecular sciences · 2024Article
- Construction of PANoptosis signature: Novel target discovery for prostate cancer immunotherapy.Molecular therapy. Nucleic acids · 2023Article
- Rational development of combination therapies for biliary tract cancers.Journal of hepatology · 2023Review
- Human Alpha 1 Antitrypsin Suppresses NF-κB Activity and Extends Lifespan in AdultBiomolecules · 2022Article
- The FGFR2c/PKCε Axis Controls MCL-1-Mediated Invasion in Pancreatic Ductal Adenocarcinoma Cells: Perspectives for Innovative Target Therapies.Biomedicines · 2022Article
- cGAS-STING signaling encourages immune cell overcoming of fibroblast barricades in pancreatic cancer.Scientific reports · 2022Article
- Article
- Tumor Microenvironment and its Implications for Antitumor Immunity in Cholangiocarcinoma: Future Perspectives for Novel Therapies.International journal of biological sciences · 2022Review
- The Application Progress of Patient-Derived Tumor Xenograft Models After Cholangiocarcinoma Surgeries.Frontiers in oncology · 2021Review
- Review
- The tumour microenvironment and immune milieu of cholangiocarcinoma.Liver international : official journal of the International Association for the Study of the Liver · 2019Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
BACKGROUND &
aimsMyeloid cell leukemia 1 (MCL1), a prosurvival member of the BCL2 protein family, has a pivotal role in human cholangiocarcinoma (CCA) cell survival. We previously reported that fibroblast growth factor receptor (FGFR) signalling mediates MCL1-dependent survival of CCA cells in vitro and in vivo. However, the mode and mechanisms of cell death in this model were not delineated.
methodsHuman CCA cell lines were treated with the pan-FGFR inhibitor LY2874455 and the mode of cell death examined by several complementary assays. Mitochondrial oxidative metabolism was examined using a XF24 extracellular flux analyser. The efficiency of FGFR inhibition in patient-derived xenografts (PDX) was also assessed.
resultsCCA cells expressed two species of MCL1, a full-length form localised to the outer mitochondrial membrane, and an N terminus-truncated species compartmentalised within the mitochondrial matrix. The pan-FGFR inhibitor LY2874455 induced non-apoptotic cell death in the CCA cell lines associated with cellular depletion of both MCL1 species. The cell death was accompanied by failure of mitochondrial oxidative metabolism and was most consistent with necrosis. Enforced expression of N terminus-truncated MCL1 targeted to the mitochondrial matrix, but not full-length MCL1 targeted to the outer mitochondrial membrane, rescued cell death and mitochondrial function. LY2874455 treatment of PDX-bearing mice was associated with tumour cell loss of MCL1 and cell necrosis.
conclusionsFGFR inhibition induces loss of matrix MCL1, resulting in cell necrosis. These observations support a heretofore unidentified, alternative MCL1 survival function, namely prevention of cell necrosis, and have implications for treatment of human CCA. LAY SUMMARY: Herein, we report that therapeutic inhibition of a cell receptor expressed by bile duct cancer cells resulted in the loss of a critical survival protein termed MCL1. Cellular depletion of MCL1 resulted in the death of the cancer cells by a process characterised by cell rupture. Cell death by this process can stimulate the immune system and has implications for combination therapy using receptor inhibition with immunotherapy.
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