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Fibroblast growth factor receptor 2 fusions as a target for treating cholangiocarcinoma.

ABSTRACT: This review will cover the role of the fibroblast growth factor pathway in the pathogenesis, targeted therapy potential and prognostic value in patients with cholangiocarcinoma (CCA).Recent studies that have identified fibroblast growth factor receptor 2 (FGFR2) fusions, prognostic implications of FGFR2 fusions, treatment strategies that target FGFR2 in CCA and future directions for understanding and targeting the FGFR2 pathway in this disease, will be discussed.Understanding the role of the FGFR2 pathway as a disease pathogenetic mechanism and the ability to develop targeted therapies and diagnostics surrounding this concept are critical elements toward developing novel targeted approaches in CCA.

SUBMITTER: Borad MJ

PROVIDER: S-EPMC4750878 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Fibroblast growth factor receptor 2 fusions as a target for treating cholangiocarcinoma.

Borad Mitesh J MJ Gores Gregory J GJ Roberts Lewis R LR

Current opinion in gastroenterology 20150501 3

<h4>Purpose of review</h4>This review will cover the role of the fibroblast growth factor pathway in the pathogenesis, targeted therapy potential and prognostic value in patients with cholangiocarcinoma (CCA).<h4>Recent findings</h4>Recent studies that have identified fibroblast growth factor receptor 2 (FGFR2) fusions, prognostic implications of FGFR2 fusions, treatment strategies that target FGFR2 in CCA and future directions for understanding and targeting the FGFR2 pathway in this disease, w ...[more]

PMID: 25763789

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Project description: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 summaryHerein, 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.

Dataset Information

Fibroblast growth factor receptor 2 fusions as a target for treating cholangiocarcinoma.

Publications

Fibroblast growth factor receptor 2 fusions as a target for treating cholangiocarcinoma.

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