Modulation of mTOR and epigenetic pathways as therapeutics in gallbladder cancer

Yang, Dong; Chen, Tao; Zhan, Ming; Xu, Sunwang; Yin, Xiangfan; Liu, Qin; Chen, Wei; Zhang, Yunhe; Liu, Dejun; Yan, Jinchun; Huang, Qihong; Wang, Jian

doi:10.1016/j.omto.2020.11.007

Cited by 14 publications

(18 citation statements)

References 46 publications

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“…Out of 92 articles, 30 were excluded due to: no data for adenocarcinoma of the gallbladder available (N = 12), overlapping cohorts (N = 8), the wrong type of article (N = 5), no genetic alteration frequency data available (N = 3), wrong study population (N = 1), and not written in English (N = 1). A total of 62 articles were included for final data extraction, describing a total of 3893 GBC samples from individual patients [ 18 , 19 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ,…”

Section: Resultsmentioning

confidence: 99%

“… ARID1A 14.3% 1/5 20% WES AC Japan Akita 2019 [ 48 ] 2/14 14% TS N.A. China Li 2017 [ 44 ] 2/47 4% WES AC China Yang 2021 [ 56 ] 2/25 8% targeted exome sequencing N.A. Korea Chae 2019 [ 79 ] 3/24 13% NGS N.A.…”

Section: Table A1mentioning

confidence: 99%

“… Japan Ebata 2021 [ 57 ] 19/144 13% WES AC India, Korea, Chile Pandey 2020 [ 46 ] 2/12 17% NGS N.A. China Li 2020 [ 47 ] 7/58 12% ultra-deep targeted NGS AC China Lin 2019 [ 70 ] 8/47 17% WES AC China Yang 2021 [ 56 ] 61/760 8% …”

Section: Table A1mentioning

confidence: 99%

“… America Okamura 2021 [ 27 ] 3/39 8% WES/WGS N.A. Japan Ebata 2021 [ 57 ] 4/47 9% WES AC China Yang 2021 [ 56 ] 22/144 15% WES AC India, Korea, Chile Pandey 2020 [ 46 ] 6/111 5% NGS N.A. America Mondaca 2019 [ 38 ] 5/12 42% …”

Section: Table A1mentioning

confidence: 99%

“… America Okamura 2021 [ 27 ] 0/32 0% targeted NGS AC Chile, Japan Narayan 2019 [ 73 ] 3/39 8% WES/WGS N.A. Japan Ebata 2021 [ 57 ] 4/47 9% WES AC China Yang 2021 [ 56 ] 3/50 6% NGS N.A. India Patel 2020 [ 39 ] 3/54 6% …”

Section: Table A1mentioning

confidence: 99%

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Gallbladder Cancer: Current Insights in Genetic Alterations and Their Possible Therapeutic Implications

Kuipers

Bitter

Boer

et al. 2021

Cancers

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Due to the fast progression in molecular technologies such as next-generation sequencing, knowledge of genetic alterations in gallbladder cancer (GBC) increases. This systematic review provides an overview of frequently occurring genetic alterations occurring in GBC and their possible therapeutic implications. A literature search was performed utilizing PubMed, EMBASE, Cochrane Library, and Web of Science. Only studies reporting genetic alterations in human GBC were included. In total, data were extracted from 62 articles, describing a total of 3893 GBC samples. Frequently detected genetic alterations (>5% in >5 samples across all studies) in GBC for which targeted therapies are available in other cancer types included mutations in ATM, ERBB2, and PIK3CA, and ERBB2 amplifications. High tumor mutational burden (TMB-H) and microsatellite instability (MSI-H) were infrequently observed in GBC (1.7% and 3.5%, respectively). For solid cancers with TMB-H or MSI-H pembrolizumab is FDA-approved and shows an objective response rates of 50% for TMB-H GBC and 41% for MSI-H biliary tract cancer. Only nine clinical trials evaluated targeted therapies in GBC directed at frequently altered genes (ERBB2, ARID1A, ATM, and KRAS). This underlines the challenges to perform such clinical trials in this rare, heterogeneous cancer type and emphasizes the need for multicenter clinical trials.

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Section: Resultsmentioning

confidence: 99%

Section: Table A1mentioning

confidence: 99%

Section: Table A1mentioning

confidence: 99%

Section: Table A1mentioning

confidence: 99%

Section: Table A1mentioning

confidence: 99%

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Gallbladder Cancer: Current Insights in Genetic Alterations and Their Possible Therapeutic Implications

Kuipers

Bitter

Boer

et al. 2021

Cancers

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Super‐Enhancer Reprograming Driven by SOX9 and TCF7L2 Represents Transcription‐Targeted Therapeutic Vulnerability for Treating Gallbladder Cancer

Yan,

Liu,

Wang

et al. 2024

Advanced Science

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Gallbladder cancer (GBC) is a highly aggressive malignancy lacking clinically available targeted therapeutic agents. Super‐enhancers (SEs) are crucial epigenetic cis‐regulatory elements whose extensive reprogramming drives aberrant transcription in cancers. To study SE in GBC, the genomic distribution of H3K27ac is profiled in multiple GBC tissue and cell line samples to establish the SE landscape and its associated core regulatory circuitry (CRC). The biliary lineage factor SOX9 and Wnt pathway effector TCF7L2, two master transcription factor (TF) candidates identified by CRC analysis, are verified to co‐occupy each other's SE region, forming a mutually autoregulatory loop to drive oncogenic SE reprogramming in a subset of GBC. The SOX9/TCF7L2 double‐high GBC cells are highly dependent on the two TFs and enriched of SE‐associated gene signatures related to stemness, ErbB and Wnt pathways. Patients with more such GBC cells exhibited significantly worse prognosis. Furthermore, SOX9/TCF7L2 double‐high GBC preclinical models are found to be susceptible to SE‐targeted CDK7 inhibition therapy in vitro and in vivo. Together, this study provides novel insights into the epigenetic mechanisms underlying the oncogenesis of a subset of GBCs with poorer prognosis and illustrates promising prognostic stratification and therapeutic strategies for treating those GBC patients in future clinical trials.

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ELF3 suppresses gallbladder cancer development through downregulation of the EREG/EGFR/mTOR complex 1 signalling pathway

Nakamura

Nishikawa

Shiokawa

et al. 2023

The Journal of Pathology

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The prognosis of gallbladder cancer (GBC) remains poor, and a better understanding of GBC molecular mechanisms is important. Genome sequencing of human GBC has demonstrated that loss‐of‐function mutations of E74‐like ETS transcription factor 3 (ELF3) are frequently observed, with ELF3 considered to be a tumour suppressor in GBC. To clarify the underlying molecular mechanisms by which ELF3 suppresses GBC development, we performed in vivo analysis using a combination of autochthonous and allograft mouse models. We first evaluated the clinical significance of ELF3 expression in human GBC tissues and found that low ELF3 expression was associated with advanced clinical stage and deep tumour invasion. For in vivo analysis, we generated Pdx1‐Cre; KrasG12D; Trp53R172H; Elf3f/f (KPCE) mice and Pdx1‐Cre; KrasG12D; Trp53R172H; Elf3wt/wt (KPC) mice as a control and analysed their gallbladders histologically. KPCE mice developed larger papillary lesions in the gallbladder than those developed by KPC mice. Organoids established from the gallbladders of KPCE and KPC mice were analysed in vitro. RNA sequencing showed upregulated expression of epiregulin (Ereg) in KPCE organoids, and western blotting revealed that EGFR/mechanical targets of rapamycin complex 1 (mTORC1) were upregulated in KPCE organoids. In addition, ChIP assays on Elf3‐overexpressing KPCE organoids showed that ELF3 directly regulated Ereg. Ereg deletion in KPCE organoids (using CRISPR/Cas9) induced EGFR/mTORC1 downregulation, indicating that ELF3 controlled EGFR/mTORC1 activity through regulation of Ereg expression. We also generated allograft mouse models using KPCE and KPC organoids and found that KPCE organoid allograft tumours exhibited poorly differentiated structures with mTORC1 upregulation and mesenchymal phenotype, which were suppressed by Ereg deletion. Furthermore, EGFR/mTORC1 inhibition suppressed cell proliferation and epithelial–mesenchymal transition in KPCE organoids. Our results suggest that ELF3 suppresses GBC development via downregulation of EREG/EGFR/mTORC1 signalling. EGFR/mTORC1 inhibition is a potential therapeutic option for GBC with ELF3 mutation. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

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Modulation of mTOR and epigenetic pathways as therapeutics in gallbladder cancer

Cited by 14 publications

References 46 publications

Gallbladder Cancer: Current Insights in Genetic Alterations and Their Possible Therapeutic Implications

Gallbladder Cancer: Current Insights in Genetic Alterations and Their Possible Therapeutic Implications

Super‐Enhancer Reprograming Driven by SOX9 and TCF7L2 Represents Transcription‐Targeted Therapeutic Vulnerability for Treating Gallbladder Cancer

ELF3 suppresses gallbladder cancer development through downregulation of the EREG/EGFR/mTOR complex 1 signalling pathway

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