RESUMO
Autoimmune liver disease (AILD) spans a spectrum of chronic disorders affecting the liver parenchyma and biliary system. Three main categories of AILD are autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). This review condenses the presentation and discussions of the Single Topic Conference (STC) on AILD that was held in Ottawa, Ontario, in November 2019. We cover generalities regarding disease presentation and clinical diagnosis; mechanistic themes; treatment paradigms; clinical trials, including approaches and challenges to new therapies; and looking beyond traditional disease boundaries. Although these diseases are considered autoimmune, the etiology and role of environmental triggers are poorly understood. AILDs are progressive and chronic conditions that affect survival and quality of life. Advances have been made in PBC treatment because second-line treatments are now available (obeticholic acid, bezafibrate); however, a significant proportion still present suboptimal response. AIH treatment has remained unchanged for several decades, and data suggest that fewer than 50% of patients achieve a complete response and as many as 80% develop treatment-related side effects. B-cell depletion therapy to treat AIH is in an early stage of development and has shown promising results. An effective treatment for PSC is urgently needed. Liver transplant remains the best option for patients who develop decompensated cirrhosis or hepatocellular carcinoma within specific criteria, but recurrent AILD might occur. Continued efforts are warranted to develop networks for AILD aimed at assessing geo-epidemiological, clinical, and biochemical differences to capture the new treatment era in Canada.
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Neoplasias Hepáticas/imunologia , Imunidade Adaptativa , Neoplasias do Sistema Biliar/tratamento farmacológico , Disbiose , Microbioma Gastrointestinal , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunidade Inata , Neoplasias Hepáticas/tratamento farmacológico , Células Supressoras Mieloides/fisiologia , Macrófagos Associados a Tumor/fisiologiaRESUMO
OBJECTIVES: Mucinous cystic neoplasm of the liver is characterized by neoplastic mucinous and/or biliary epithelium surrounded by ovarian-type stroma. Immunohistochemical studies have shown that the ovarian-type stroma expresses estrogen receptor, suggesting potential hormonal responsiveness. The molecular biology of mucinous cystic neoplasm of the liver remains poorly studied. METHODS: Transcriptome sequencing and immunohistochemistry were performed on a series of mucinous cystic neoplasms. RESULTS: Mucinous cystic neoplasm of the liver exhibited significantly increased RNA expression of ovarian stromal markers WT1, PR, and ER2 and sex cord stromal markers SF-1, inhibin-α, and calretinin compared with nonneoplastic liver. Immunohistochemistry confirmed the RNA-level data. Evidence for sex hormone biosynthesis was identified by significant overexpression of multiple estrogen biosynthetic enzymes. Expression of 17ß-hydroxysteroid dehydrogenase 1 was confirmed immunohistochemically. Pathway analysis also identified significant upregulation of the hedgehog and Wnt pathways and significant downregulation of T-helper 1 and T-helper 2 pathways. CONCLUSIONS: Mucinous cystic neoplasm of the liver recapitulates ovarian stroma at the morphologic, DNA, RNA, and protein levels. These data support the concept that this tumor likely arises from ectopic primitive gonadal tissue and/or stromal cells with capacity to transdifferentiate to ovarian cortical cells.
Assuntos
Cistadenoma Mucinoso/química , Cistadenoma Mucinoso/genética , Perfilação da Expressão Gênica , Neoplasias Hepáticas/química , Neoplasias Hepáticas/genética , Biomarcadores Tumorais/análise , Cistadenoma Mucinoso/patologia , Análise Mutacional de DNA , Estrogênios/biossíntese , Estrogênios/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Proteínas Hedgehog/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Imunofenotipagem , Fígado/patologia , Neoplasias Hepáticas/patologia , Ovário/patologia , Análise de Sequência de DNA , Células Estromais/patologia , Via de Sinalização Wnt/genéticaRESUMO
Cholangiocarcinoma (CCA) includes a cluster of highly heterogeneous biliary malignant tumours that can arise at any point of the biliary tree. Their incidence is increasing globally, currently accounting for ~15% of all primary liver cancers and ~3% of gastrointestinal malignancies. The silent presentation of these tumours combined with their highly aggressive nature and refractoriness to chemotherapy contribute to their alarming mortality, representing ~2% of all cancer-related deaths worldwide yearly. The current diagnosis of CCA by non-invasive approaches is not accurate enough, and histological confirmation is necessary. Furthermore, the high heterogeneity of CCAs at the genomic, epigenetic and molecular levels severely compromises the efficacy of the available therapies. In the past decade, increasing efforts have been made to understand the complexity of these tumours and to develop new diagnostic tools and therapies that might help to improve patient outcomes. In this expert Consensus Statement, which is endorsed by the European Network for the Study of Cholangiocarcinoma, we aim to summarize and critically discuss the latest advances in CCA, mostly focusing on classification, cells of origin, genetic and epigenetic abnormalities, molecular alterations, biomarker discovery and treatments. Furthermore, the horizon of CCA for the next decade from 2020 onwards is highlighted.
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Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/terapia , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/terapia , Neoplasias dos Ductos Biliares/etiologia , Colangiocarcinoma/etiologia , HumanosRESUMO
The Hippo pathway effector Yes-associated protein (YAP) is localized to the nucleus and transcriptionally active in a number of tumor types, including a majority of human cholangiocarcinomas. YAP activity has been linked to chemotherapy resistance and has been shown to rescue KRAS and BRAF inhibition in RAS/RAF-driven cancers; however, the underlying mechanisms of YAP-mediated chemoresistance have yet to be elucidated. Herein, we report that the tyrosine phosphatase SHP2 directly regulates the activity of YAP by dephosphorylating pYAPY357 even in the setting of RAS/RAF mutations, and that diminished SHP2 phosphatase activity is associated with chemoresistance in cholangiocarcinomas. A screen for YAP-interacting tyrosine phosphatases identified SHP2, and characterization of cholangiocarcinomas cell lines demonstrated an inverse relationship between SHP2 levels and pYAPY357. Human sequencing data demonstrated lower SHP2 levels in cholangiocarcinomas tumors as compared with normal liver. Cell lines with low SHP2 expression and higher levels of pYAPY357 were resistant to gemcitabine and cisplatin. In cholangiocarcinomas cells with high levels of SHP2, pharmacologic inhibition or genetic deletion of SHP2 increased YAPY357 phosphorylation and expression of YAP target genes, including the antiapoptotic regulator MCL1, imparting resistance to gemcitabine and cisplatin. In vivo evaluation of chemotherapy sensitivity demonstrated significant resistance in xenografts with genetic deletion of SHP2, which could be overcome by utilizing an MCL1 inhibitor. IMPLICATIONS: These findings demonstrate a role for SHP2 in regulating YAP activity and chemosensitivity, and suggest that decreased phosphatase activity may be a mechanism of chemoresistance in cholangiocarcinoma via a MCL1-mediated mechanism.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Colangiocarcinoma/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Fatores de Transcrição/metabolismo , Animais , Colangiocarcinoma/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Transfecção , Proteínas de Sinalização YAPRESUMO
Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy with a poor overall prognosis. There is a critical need to develop effective targeted therapies for the treatment of this lethal disease. In an effort to address this challenge, preclinical in vivo studies have become paramount in understanding CCA carcinogenesis, progression, and therapy. Various CCA animal models exist including carcinogen-based models in which animals develop CCA after exposure to a carcinogen, genetically engineered mouse models in which genetic changes are induced in mice leading to CCA, murine syngeneic orthotopic models, as well as xenograft tumors derived from xenotransplantation of CCA cells, organoids, and patient-derived tissue. Each type has distinct advantages as well as shortcomings. In the ideal animal model of CCA, the tumor arises from the biliary tract in an immunocompetent host with a species-matched tumor microenvironment. Such a model would also be time-efficient, recapitulate the genetic and histopathological features of human CCA, and predict therapeutic response in humans. Recently developed biliary tract transduction and orthotopic syngeneic transplant mouse models encompass several of these elements. Herein, we review the different animal models of CCA, their advantages and deficiencies, as well as features which mimic human CCA.
Assuntos
Neoplasias dos Ductos Biliares/etiologia , Colangiocarcinoma/etiologia , Modelos Animais de Doenças , Animais , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , Colestase/complicações , Edição de Genes/métodos , Humanos , Ensaios Antitumorais Modelo de Xenoenxerto/métodosRESUMO
Cholangiocarcinoma (CCA) represents a heterogeneous group of epithelial tumours that are classified according to anatomical location as intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA). Although surgical resection and liver transplantation following neoadjuvant therapy are potentially curative options for a subset of patients with early-stage disease, the currently available medical therapies for CCA have limited efficacy. Immunotherapeutic strategies such as immune checkpoint blockade (ICB) harness the host immune system to unleash an effective and durable antitumour response in a subset of patients with a variety of malignancies. However, response to ICB monotherapy has been relatively disappointing in CCA. CCAs are desmoplastic tumours with an abundant tumour immune microenvironment (TIME) that contains immunosuppressive innate immune cells such as tumour-associated macrophages and myeloid-derived suppressor cells. A subset of CCAs may be classified as immune 'hot' tumours with a high density of CD8+ T cells and enhanced expression of immune checkpoint molecules. Immune 'hot' tumour types are associated with higher response rates to ICB. However, the suboptimal response rates to ICB monotherapy in human clinical trials of CCA imply that the preponderance of CCAs are immune 'cold' tumours with a non-T cell infiltrated TIME. An enhanced comprehension of the immunobiology of CCA, particularly the innate immune response to CCA, is essential in the effort to develop effective combination immunotherapeutic strategies that can target a larger subset of CCAs.
RESUMO
The diagnosis of malignant biliary strictures remains problematic, especially in the perihilar region and in primary sclerosing cholangitis (PSC). Conventional cytology obtained during endoscopic retrograde cholangiography (ERC)-guided brushings of biliary strictures is suboptimal due to limited sensitivity, albeit it remains the gold standard with a high specificity. Emerging technologies are being developed and validated to address this pressing unmet patient need. Such technologies include enhanced visualization of the biliary tree by cholangioscopy, intraductal ultrasound, and confocal laser endomicroscopy. Conventional cytology can be aided by employing complementary and advanced cytologic techniques such as fluorescent in situ hybridization (FISH), and this technique should be widely adapted. Interrogation of bile and serum by examining extracellular vesicle number and cargo, and exploiting next-generation sequencing and proteomic technologies, is also being explored. Examination of circulating cell-free deoxyribonucleic acid (cfDNA) for differentially methylated regions is a promising test which is being rigorously validated. The special expertise required for these analyses has to date hampered their validation and adaptation. Herein, we will review these emerging technologies to inform the reader of the progress made and encourage further studies, as well as adaptation of validated approaches.
Assuntos
Neoplasias dos Ductos Biliares/diagnóstico , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Diagnóstico por Imagem/tendências , Detecção Precoce de Câncer/tendências , Endoscopia do Sistema Digestório/tendências , Tumor de Klatskin/diagnóstico , Técnicas de Diagnóstico Molecular/tendências , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Difusão de Inovações , Humanos , Tumor de Klatskin/genética , Tumor de Klatskin/patologia , Valor Preditivo dos Testes , PrognósticoRESUMO
Deregulated Hippo pathway signaling is associated with aberrant activation of the downstream effector yes-associated protein (YAP), an emerging key oncogenic mediator in cholangiocarcinoma (CCA). In our prior work, we have demonstrated that biliary transduction of YAP along with Akt as a permissive factor induces CCA in mice. To further delineate the mechanisms associated with YAP-associated biliary oncogenesis, we have established seven malignant murine cell lines from our YAP-driven murine CCA model. These cells express the CCA markers SRY (Sex Determining Region Y)-Box 9 (SOX9), cytokeratin (CK)-7 and 19 but lack hepatocyte nuclear factor 4 alpha and alpha-smooth muscle actin, markers of hepatocellular carcinoma and cancer-associated fibroblasts, respectively. Notably, the murine CCA cells can be readily implanted into mouse livers with resultant orthotopic tumor formation. In this unique syngeneic orthotopic murine model, tumors exhibit histopathologic features resembling human CCA. We analyzed transcriptome data from YAP-associated parent CCA tumor nodules and identified a gene expression pattern associated with chromosomal instability, known as CIN25. Similarly, mate-pair sequencing of the murine CCA cells revealed chromosomal missegregation with gains and losses of several whole chromosomes demonstrating aneuploidy. Of the CIN25 genes, forkhead box M1 (Foxm1), a key cell cycle regulator, was the most significantly upregulated CIN25 gene product. Accordingly, small interfering RNA (siRNA)-mediated silencing of YAP as well as FOXM1 inhibition with thiostrepton induced CCA cell death. These preclinical data imply a role for YAP-mediated chromosomal instability in cholangiocarcinoma, and suggest FOXM1 inhibition as a therapeutic target for CCA.
RESUMO
BACKGROUND & AIMS: Myeloid 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. METHODS: Human 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. RESULTS: CCA 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. CONCLUSIONS: FGFR 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.
Assuntos
Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/metabolismo , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/metabolismo , Indazóis/farmacologia , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Animais , Neoplasias dos Ductos Biliares/patologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Colangiocarcinoma/patologia , Humanos , Indóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Necrose , Oxirredução , Sulfonamidas/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Cholangiocarcinoma is a disease entity comprising diverse epithelial tumours with features of cholangiocyte differentiation: cholangiocarcinomas are categorized according to anatomical location as intrahepatic (iCCA), perihilar (pCCA), or distal (dCCA). Each subtype has a distinct epidemiology, biology, prognosis, and strategy for clinical management. The incidence of cholangiocarcinoma, particularly iCCA, has increased globally over the past few decades. Surgical resection remains the mainstay of potentially curative treatment for all three disease subtypes, whereas liver transplantation after neoadjuvant chemoradiation is restricted to a subset of patients with early stage pCCA. For patients with advanced-stage or unresectable disease, locoregional and systemic chemotherapeutics are the primary treatment options. Improvements in external-beam radiation therapy have facilitated the treatment of cholangiocarcinoma. Moreover, advances in comprehensive whole-exome and transcriptome sequencing have defined the genetic landscape of each cholangiocarcinoma subtype. Accordingly, promising molecular targets for precision medicine have been identified, and are being evaluated in clinical trials, including those exploring immunotherapy. Biomarker-driven trials, in which patients are stratified according to anatomical cholangiocarcinoma subtype and genetic aberrations, will be essential in the development of targeted therapies. Targeting the rich tumour stroma of cholangiocarcinoma in conjunction with targeted therapies might also be useful. Herein, we review the evolving developments in the epidemiology, pathogenesis, and management of cholangiocarcinoma.
Assuntos
Colangiocarcinoma/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Terapia de Alvo Molecular , Medicina de Precisão , Adulto , Diferenciação Celular/genética , Quimiorradioterapia/efeitos adversos , Colangiocarcinoma/classificação , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Humanos , Neoplasias Hepáticas/classificação , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Transplante de Fígado/tendências , Terapia Neoadjuvante , PrognósticoRESUMO
Cholangiocarcinoma (CCA) represents a diverse group of epithelial cancers associated with the biliary tract, and can best be stratified anatomically into intrahepatic (iCCA), perihilar (pCCA) and distal (dCCA) subsets. Molecular profiling has identified genetic aberrations associated with these anatomic subsets. For example, IDH catalytic site mutations and constitutively active FGFR2 fusion genes are predominantly identified in iCCA, whereas KRAS mutations and PRKACB fusions genes are identified in pCCA and dCCA. Clinical trials targeting these specific driver mutations are in progress. However, The Tumor Genome Atlas (TCGA) marker analysis of CCA also highlights the tremendous molecular heterogeneity of this cancer rendering comprehensive employment of targeted therapies challenging. CCA also display a rich tumor microenvironment which may be easier to target. For example, targeting cancer associated fibroblasts for apoptosis with BH3-mimetics and/or and reversing T-cell exhaustion with immune check point inhibitors may help aid in the treatment of this otherwise devastating malignancy. Combinatorial therapy attacking the tumor microenvironment plus targeted therapy may help advance treatment for CCA. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias dos Ductos Biliares/terapia , Biomarcadores Tumorais/antagonistas & inibidores , Colangiocarcinoma/terapia , Terapia de Alvo Molecular/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/imunologia , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares/citologia , Ductos Biliares/patologia , Ductos Biliares/cirurgia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Quimiorradioterapia Adjuvante/métodos , Colangiocarcinoma/genética , Colangiocarcinoma/imunologia , Colangiocarcinoma/patologia , Receptores Coestimuladores e Inibidores de Linfócitos T/antagonistas & inibidores , Receptores Coestimuladores e Inibidores de Linfócitos T/imunologia , Receptores Coestimuladores e Inibidores de Linfócitos T/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Humanos , Mutação , Terapia Neoadjuvante/métodos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genéticaRESUMO
Cholangiocarcinomas (CCAs) are diverse epithelial tumors arising from the liver or large bile ducts with features of cholangiocyte differentiation. CCAs are classified anatomically into intrahepatic (iCCA), perihilar (pCCA), and distal CCA (dCCA). Each subtype has distinct risk factors, molecular pathogenesis, therapeutic options, and prognosis. CCA is an aggressive malignancy with a poor overall prognosis and median survival of less than 2years in patients with advanced disease. Potentially curative surgical treatment options are limited to the subset of patients with early-stage disease. Presently, the available systemic medical therapies for advanced or metastatic CCA have limited therapeutic efficacy. Molecular alterations define the differences in biological behavior of each CCA subtype. Recent comprehensive genetic analysis has better characterized the genomic and transcriptomic landscape of each CCA subtype. Promising candidates for targeted, personalized therapy have emerged, including potential driver fibroblast growth factor receptor (FGFR) gene fusions and somatic mutations in isocitrate dehydrogenase (IDH)1/2 in iCCA, protein kinase cAMP-activated catalytic subunit alpha (PRKACA) or beta (PRKACB) gene fusions in pCCA, and ELF3 mutations in dCCA/ampullary carcinoma. A precision genomic medicine approach is dependent on an enhanced understanding of driver mutations in each subtype and stratification of patients according to their genetic drivers. We review the current genomic landscape of CCA, the potentially actionable molecular aberrations in each CCA subtype, and the role of immunotherapy in CCA.
Assuntos
Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Terapia de Alvo Molecular , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/mortalidade , Colangiocarcinoma/genética , Colangiocarcinoma/mortalidade , Fator de Crescimento de Hepatócito/antagonistas & inibidores , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Imunoterapia , Isocitrato Desidrogenase/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidoresRESUMO
Cholangiocarcinomas (CCAs) are heterogeneous tumors arising from the biliary tract with features of cholangiocyte differentiation. CCAs are aggressive tumors with limited treatment options and poor overall survival. Only a subset of CCA patients with early stage disease can avail potentially curative treatment options. For advanced biliary tract tumors, currently there are limited effective treatment modalities. Recent advances have provided greater insight into the genomic landscape of CCAs. The fibroblast growth factor receptor (FGFR) pathway is involved in key cellular processes essential to survival and differentiation. Accordingly, aberrant FGFR signaling has significant oncogenic potential. Recent discovery of FGFR2 gene fusions in CCA has heightened interest in FGFR inhibition in advanced biliary tract cancer. These findings have served as a catalyst for ongoing clinical investigation of FGFR inhibition in CCA patients with various FGFR signaling abnormalities. Herein, we review FGFR aberrations in CCA and their prognostic implications, FGFR targeting as a viable therapeutic option in advanced biliary tract malignancies, and future directions for development of combination approaches utilizing FGFR inhibition.
RESUMO
Herein, we have identified cross-talk between the Hippo and fibroblast growth factor receptor (FGFR) oncogenic signaling pathways in cholangiocarcinoma (CCA). Yes-associated protein (YAP) nuclear localization and up-regulation of canonical target genes was observed in CCA cell lines and a patient-derived xenograft (PDX). Expression of FGFR1, -2, and -4 was identified in human CCA cell lines, driven, in part, by YAP coactivation of TBX5. In turn, FGFR signaling in a cell line with minimal basal YAP expression induced its cellular protein expression and nuclear localization. Treatment of YAP-positive CCA cell lines with BGJ398, a pan-FGFR inhibitor, resulted in a decrease in YAP activation. FGFR activation of YAP appears to be driven largely by FGF5 activation of FGFR2, as siRNA silencing of this ligand or receptor, respectively, inhibited YAP nuclear localization. BGJ398 treatment of YAP-expressing cells induced cell death due to Mcl-1 depletion. In a YAP-associated mouse model of CCA, expression of FGFR 1, 2, and 4 was also significantly increased. Accordingly, BGJ398 treatment was tumor-suppressive in this model and in a YAP-positive PDX model. These preclinical data suggest not only that the YAP and Hippo signaling pathways culminate in an Mcl-1-regulated tumor survival pathway but also that nuclear YAP expression may be a biomarker to employ in FGFR-directed therapy.