HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target?

Galdy, Salvatore; Lamarca, Ángela; McNamara, Mairéad G.; Hubner, Richard A; Cella, Chiara Alessandra; Fazio, Nicola; Valle, Juan W.

doi:10.1007/s10555-016-9645-x

Cited by 130 publications

(99 citation statements)

References 83 publications

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“…( 32 ) Specifically, HER2 is a well‐described predictive biomarker for positive anti‐HER2 therapy response in breast and gastric cancer and, lately, in CCA. ( 33,34 ) Our first results showed dramatically increased ErbB2 protein and mRNA levels in livers of NEMO ∆hepa /JNK Δhepa compared with NEMO ∆hepa hepatic tissue (Fig. 5B‐D).…”

Section: Resultsmentioning

confidence: 72%

Loss of c‐Jun N‐terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling Cholangiocarcinoma

et al. 2020

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Targeted inhibition of the c-Jun N-terminal kinases ( JNKs) has shown therapeutic potential in intrahepatic cholangiocarcinoma (CCA)-related tumorigenesis. However, the cell-type-specific role and mechanisms triggered by JNK in liver parenchymal cells during CCA remain largely unknown. Here, we aimed to investigate the relevance of JNK1 and JNK2 function in hepatocytes in two different models of experimental carcinogenesis, the dethylnitrosamine (DEN) model and in nuclear factor kappa B essential modulator (NEMO) hepatocyte-specific knockout (Δhepa) mice, focusing on liver damage, cell death, compensatory proliferation, fibrogenesis, and tumor development. Moreover, regulation of essential genes was assessed by reverse transcription polymerase chain reaction, immunoblottings, and immunostainings. Additionally, specific Jnk2 inhibition in hepatocytes of NEMO Δhepa /JNK1 Δhepa mice was performed using small interfering (si) RNA (siJnk2) nanodelivery. Finally, active signaling pathways were blocked using specific inhibitors. Compound deletion of Jnk1 and Jnk2 in hepatocytes diminished hepatocellular carcinoma (HCC) in both the DEN model and in NEMO Δhepa mice but in contrast caused massive proliferation of the biliary ducts. Indeed, Jnk1/2 deficiency in hepatocytes of NEMO Δhepa (NEMO Δhepa /JNK Δhepa ) animals caused elevated fibrosis, increased apoptosis, increased compensatory proliferation, and elevated inflammatory cytokines expression but reduced HCC. Furthermore, siJnk2 treatment in NEMO Δhepa /JNK1 Δhepa mice recapitulated the phenotype of NEMO Δhepa /JNK Δhepa mice. Next, we sought to investigate the impact of molecular pathways in response to compound JNK deficiency in NEMO Δhepa mice. We found that NEMO Δhepa /JNK Δhepa livers exhibited overexpression of the interleukin-6/signal transducer and activator of transcription 3 pathway in addition to epidermal growth factor receptor (EGFR)-rapidly accelerated fibrosarcoma (Raf )-mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) cascade. The functional relevance was tested by administering lapatinib, which is a dual tyrosine kinase inhibitor of erythroblastic oncogene B-2 (ErbB2) and EGFR signaling, to NEMO Δhepa /JNK Δhepa mice. Lapatinib effectively inhibited cystogenesis, improved transaminases, and effectively blocked EGFR-Raf-MEK-ERK signaling. Conclusion: We define a novel function of JNK1/2 in cholangiocyte hyperproliferation. This opens new therapeutic avenues devised to inhibit pathways of cholangiocarcinogenesis. (Hepatology Communications 2020;4:834-851). Bile duct hyperplasia and aberrant cholangiocyte growth can result in hepatic cystogenesis, differentially diagnosed on the basis of cholangioma, cholangiofibrosis, intrahepatic cholangiocarcinoma (CCA), and oval cell hyperplasia. (1,2) CCA, a malignancy that arises in the setting of chronic inflammation of biliary epithelium cells, has an increasing incidence and is the second most common primary Abbreviations: α-SMA, alpha smooth muscle actin; Δhepa, hepatocy...

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Section: Resultsmentioning

confidence: 72%

Loss of c‐Jun N‐terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling Cholangiocarcinoma

et al. 2020

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“…Rate of HER-2 over-expression was found to be higher in ECC (17.4%) compared to ICC (4.8%) in a recent systematic review and meta-analysis published by Galdy et al in 2016 (165). Good correlation between overexpression and gene amplification (75%) has been shown (151).…”

Section: Emerging Therapiesmentioning

confidence: 95%

“…HER-2 (v-ERB-B2, erythroblastic leukaemia viral oncogene homolog-2) over-expression and gene amplification is also described in BTCs with a higher incidence in gallbladder cancer (19%) (165). Rate of HER-2 over-expression was found to be higher in ECC (17.4%) compared to ICC (4.8%) in a recent systematic review and meta-analysis published by Galdy et al in 2016 (165).…”

Section: Emerging Therapiesmentioning

confidence: 99%

“…Those without range come from single reports. Extracted from: Desphande et al BMC Cancer 2011(105), Borger et al The Oncologist 2012(104), Voss et al Human Pathology 2013(208), Ross et al The Oncologist 2014(52), Ong et al Nature Genetics 2012(45), Graham et al Human Pathology 2014(126), Arai et al Hepatology 2014(81), Sia et al Nature Communications 2015(82), Javle et al Cancer 2016(53), Zou et al Nature Communications 2014(62), Li et al Nat Genet 2014(103), Zhu et al Ann Surg Oncol 2014(118), Sia Gastroenterology 2013(54), Jiao et al Nature Genetics 2013(119), Chan-on et al Nature Genetics 2013(46), Wang et al Oncogene 2013(117), Wu et al Cancer Discovery 2013(79), Ross et al Journal of Clinical Oncology 2015(51), Nakamura et al Nature Genetics 2015(89), Borad et al PLoS Genetics 2014(48), Randall et al Journal of Clinical Oncology 2015(50), Galdy et al Cancer and Metastases Reviews 2016(165), Churi et al PlosOne 2014(83), Turner et al Nature Reviews in Cancer 2010(127), Pai et al European Journal of Cancer Prevention 2011(203), Riener et al Genes Chromosomes and Cancer 2008(212). ICC: intrahepatic cholangiocarcinoma, ECC: extrahepatic cholangiocarcinoma, GBCA gallbladder cancer.…”

Section: Figurementioning

confidence: 99%

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New Horizons for Precision Medicine in Biliary Tract Cancers

et al. 2017

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Biliary tract cancers (BTCs), including cholangiocarcinoma and gallbladder cancer, are poor-prognosis and low-incidence cancers, although the incidence of intrahepatic cholangiocarcinoma is rising. A minority of patients presents with resectable disease; however, relapse rates are high; benefit from adjuvant capecitabine chemotherapy has been suggested. Cisplatin/gemcitabine combination chemotherapy has emerged as the reference first-line treatment regimen; there is no standard second-line therapy. Selected patients may be suitable for liver-directed therapy (e.g. radioembolization or external beam radiation); pending confirmation of benefit in randomized studies. Initial trials targeting the epithelial growth factor receptor and angiogenesis pathways have failed to deliver new treatments. Emerging data from next generation sequencing analyses have identified actionable mutations (e.g. FGFR fusion rearrangements and IDH-1 and -2 mutations) with several targeted drugs entering clinical development with encouraging results. The role of systemic therapies, including targeted therapies and immunotherapy for BTC is rapidly evolving and the subject of this review.

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“…HBV, HCV and chronic cholangitis contribute to the majority of the 70,000 ICC cases emerging in 14 . Due to low mortality and the number of patients with specific ERBB2 amplifications, a previous clinical trial (NCT00478140) was halted.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive molecular profiling of intrahepatic cholangiocarcinoma in the Chinese population and therapeutic experience

Wang

Zhu²,

Zhao³

et al. 2020

Preprint

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PURPOSE: The genomic alterations of intrahepatic cholangiocarcinoma (ICC) in the Chinese population have not been fully revealed. Molecular profiling may provide a reference for clinical management, especially targeted therapy. METHODS: A retrospective study was conducted in 122 ICC patients. All patients had results of next-generation sequencing (NGS) assays that analyzed 417 cancer-associated genes. The genetic characteristics, clinical management and therapeutic responses were analyzed. RESULTS: The most commonly mutated genes were TP53 (34%), KRAS (25%) and ARID1A (17%). Targeted agents were used referring to molecular profiling, with a combination of chemotherapy. Twenty-two patients with wild-type KRAS/NRAS/BRAF were treated with cetuximab. The disease control and response rates were 78% and 47%, respectively, which were higher than those achieved with chemotherapy alone (72% and 11%, P=0.16). Fifty-four patients underwent anti-VEGF treatment with bevacizumab. The disease control and response rates were 85% and 60%, respectively. Better therapeutic efficiency (P=0.001) and longer progression-free survival (PFS; 15.4 vs 6.7 months, P=0.04) were observed in the bevacizumab-treated group than in the chemotherapy alone group. The PFS of ten patients who underwent hepatectomy after combined treatment with chemotherapy and bevacizumab was longer than that of 139 patients who underwent surgical treatment (28.9 vs 18.0 months, P=0.03). Two patients (1.6%) had signatures of microsatellite instability (MSI-H), and both benefited from immunotherapy. CONCLUSIONS: This study provides an overview of genetic alterations in Chinese ICC patients and indicates the potential clinical implications for NGS-based personalized therapies.

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HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target?

Cited by 130 publications

References 83 publications

Loss of c‐Jun N‐terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling Cholangiocarcinoma

Loss of c‐Jun N‐terminal Kinase 1 and 2 Function in Liver Epithelial Cells Triggers Biliary Hyperproliferation Resembling Cholangiocarcinoma

New Horizons for Precision Medicine in Biliary Tract Cancers

Comprehensive molecular profiling of intrahepatic cholangiocarcinoma in the Chinese population and therapeutic experience

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