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      Drug Design, Development and Therapy (submit here)

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      Inhibitors Targeting YAP in Gastric Cancer: Current Status and Future Perspectives

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          Abstract

          Gastric cancer (GC) is one of the most common cancers globally, threatening global health. The deregulation of the Hippo signaling pathway has been discovered in GC and may be related to cancer development, proliferation, metastasis, and drug resistance. Yes-associated protein (YAP), as a downstream effector of the Hippo signaling pathway and a crucial co-transcription factor in the nucleus, is a promising and vital potential drug target for the treatment of GC. A series of drugs or compounds that inhibit YAP has been developed or confirmed. Therefore, this review will focus on summarizing the drugs and small-molecule inhibitors that have been reported to inhibit YAP and discuss the clinical prospects of YAP inhibitors in GC.

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          Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

          Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)
          This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.
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            Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP.

            Yi Liu-Chittenden, Bo Huang, Joong Sup Shim … (2012)
            The Drosophila TEAD ortholog Scalloped is required for Yki-mediated overgrowth but is largely dispensable for normal tissue growth, suggesting that its mammalian counterpart may be exploited for selective inhibition of oncogenic growth driven by YAP hyperactivation. Here we test this hypothesis genetically and pharmacologically. We show that a dominant-negative TEAD molecule does not perturb normal liver growth but potently suppresses hepatomegaly/tumorigenesis resulting from YAP overexpression or Neurofibromin 2 (NF2)/Merlin inactivation. We further identify verteporfin as a small molecule that inhibits TEAD-YAP association and YAP-induced liver overgrowth. These findings provide proof of principle that inhibiting TEAD-YAP interactions is a pharmacologically viable strategy against the YAP oncoprotein.
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              Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer.

              Fa-Xing Yu, Bin Zhao, Kun-Liang Guan (2015)
              Two decades of studies in multiple model organisms have established the Hippo pathway as a key regulator of organ size and tissue homeostasis. By inhibiting YAP and TAZ transcription co-activators, the Hippo pathway regulates cell proliferation, apoptosis, and stemness in response to a wide range of extracellular and intracellular signals, including cell-cell contact, cell polarity, mechanical cues, ligands of G-protein-coupled receptors, and cellular energy status. Dysregulation of the Hippo pathway exerts a significant impact on cancer development. Further investigation of the functions and regulatory mechanisms of this pathway will help uncovering the mystery of organ size control and identify new targets for cancer treatment.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Drug Des Devel Ther
                Journal ID (iso-abbrev): Drug Des Devel Ther
                Journal ID (publisher-id): dddt
                Journal ID (pmc): dddt
                Title: Drug Design, Development and Therapy
                Publisher: Dove
                ISSN (Electronic): 1177-8881
                Publication date (Electronic): 09 June 2021
                Publication date Collection: 2021
                Volume: 15
                Pages: 2445-2456
                Affiliations
                [1 ]Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University , Shenyang, Liaoning Province, 110001, People’s Republic of China
                Author notes
                Correspondence: Zhenning Wang; Yan Xu Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University , Shenyang, Liaoning Province, 110001, People’s Republic of China Email josieon826@sina.cn; yanxu@cmu.edu.cn
                Article
                Publisher ID: 308377
                DOI: 10.2147/DDDT.S308377
                PMC ID: 8203099
                PubMed ID: 34140763
                SO-VID: 6210ad75-825b-4cd3-9e88-c5e0c9f76eeb
                Copyright statement: © 2021 Yong et al.
                License:

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                Date received : 25 February 2021
                Date accepted : 19 May 2021
                Page count
                Figures: 1, Tables: 4, References: 102, Pages: 12
                Funding
                Funded by: National Science Foundation of China, open-funder-registry 10.13039/501100001809;
                This work was supported by the National Science Foundation of China (Liaoning Province Joint Fund) (No. U1908207).
                Categories
                Subject: Review

                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: gastric adenocarcinoma,yes-associated protein,hippo pathway,small molecule inhibitor,targeted therapy
                Data availability:
                ScienceOpen disciplines: Pharmacology & Pharmaceutical medicine
                Keywords: gastric adenocarcinoma, yes-associated protein, hippo pathway, small molecule inhibitor, targeted therapy

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