NOTUM is a potential pharmacodynamic biomarker of Wnt pathway inhibition

Madan, Babita; Zhao, Ke; Lei, Zheng Deng; Oliver, Frois Ashley; Oshima, Masanobu; Lee, May Ann; Rozen, Steve; Virshup, David M.

doi:10.18632/oncotarget.7157

Cited by 21 publications

(17 citation statements)

References 20 publications

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“…CFPAC-1 has no known mutation in Wnt pathway but is sensitive to β-catenin knockdown ( Supplementary Fig. S1), as well as PORCN inhibitor [35]. EGI-1, a cholangiocarcinoma cell line with a RSPO3 translocation that confers Wnt dependency, was also included in the drug combination study ( Supplementary Fig.…”

Section: A Drug Combination Study Reveals the Synergy Between Porcn Imentioning

confidence: 99%

PORCN inhibition synergizes with PI3K/mTOR inhibition in Wnt-addicted cancers

et al. 2019

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Pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) is aggressive and lethal. Although there is an urgent need for effective therapeutics in treating pancreatic cancer, none of the targeted therapies tested in clinical trials to date significantly improve its outcome. PORCN inhibitors show efficacy in preclinical models of Wnt-addicted cancers, including RNF43mutant pancreatic cancers and have advanced to clinical trials. In this study, we aimed to develop drug combination strategies to further enhance the therapeutic efficacy of the PORCN inhibitor ETC-159. To identify additional druggable vulnerabilities in Wnt-driven pancreatic cancers, we performed an in vivo CRISPR loss-of-function screen. CTNNB1, KRAS, and MYC were reidentified as key oncogenic drivers. Notably, glucose metabolism pathway genes were important in vivo but less so in vitro. Knockout of multiple genes regulating PI3K/mTOR signaling impacted the growth of Wnt-driven pancreatic cancer cells in vivo. Importantly, multiple PI3K/mTOR pathway inhibitors in combination with ETC-159 synergistically suppressed the growth of multiple Wnt-addicted cancer cell lines in soft agar. Furthermore, the combination of the PORCN inhibitor ETC-159 and the pan-PI3K inhibitor GDC-0941 potently suppressed the in vivo growth of RNF43mutant pancreatic cancer xenografts. This was largely due to enhanced suppressive effects on both cell proliferation and glucose metabolism. These findings demonstrate that dual PORCN and PI3K/mTOR inhibition is a potential strategy for treating Wnt-driven pancreatic cancers.

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Section: A Drug Combination Study Reveals the Synergy Between Porcn Imentioning

confidence: 99%

PORCN inhibition synergizes with PI3K/mTOR inhibition in Wnt-addicted cancers

et al. 2019

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“…Recent data show that cleavage of the essential palmitoleate moiety by the carboxylesterase Notum is an important regulatory process to reduce Wnt signalling range [ 25 ]. Extracellular levels of Notum in the blood serves as a biomarker for Wnt-driven cancer [ 26 ]. In the case of glycosylation, the number of glycosylation residues varies between the different Wnts and it is possible this modification is dispensable for its activity [ 27 , 28 ].…”

Section: Hh and Wnt Molecules Are Both Lipid-modified And Strongly Asmentioning

confidence: 99%

From top to bottom: Cell polarity in Hedgehog and Wnt trafficking

et al. 2018

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Spatial organization of membrane domains within cells and cells within tissues is key to the development of organisms and the maintenance of adult tissue. Cell polarization is crucial for correct cell–cell signalling, which, in turn, promotes cell differentiation and tissue patterning. However, the mechanisms linking internal cell polarity to intercellular signalling are just beginning to be unravelled. The Hedgehog (Hh) and Wnt pathways are major directors of development and their malfunction can cause severe disorders like cancer. Here we discuss parallel advances into understanding the mechanism of Hedgehog and Wnt signal dissemination and reception. We hypothesize that cell polarization of the signal-sending and signal-receiving cells is crucial for proper signal spreading and activation of the pathway and, thus, fundamental for development of multicellular organisms.

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“…Earlier studies have shown that NOTUM regulates development in Drosophila, while its function in mammals was only recently characterized (25). NOTUM is overexpressed in hepatocellular carcinoma (28) and is also related to gastric cancer (34). These observations suggest that NOTUM has a role in other cancer types but do not provide any association between NOTUM and CRC.…”

Section: Discussionmentioning

confidence: 94%

NOTUM Is Involved in the Progression of Colorectal Cancer

Yoon

Kim

et al. 2018

Cancer Genomics Proteomics

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Background: There are limitations to current colorectal cancer (CRC)-specific diagnostic methods and therapies. Tumorigenesis proceeds because of interaction between cancer cells and various surrounding cells; discovering new molecular mediators through studies of the CRC secretome is a promising approach for the development of CRC diagnostics and therapies. Materials and Methods: A comparative secretomic analysis was performed using primary and metastatic human isogenic CRC cells. Proliferation was determined by MTT and thymidine incorporation assay, migration was determined by wound-healing assay (ELISA). The level of palmitoleoyl-protein carboxylesterase (NOTUM) in plasma from patients with CRC was determined by enzymelinked immunosorbent assay. Results: NOTUM expression was increased in metastatic cells. Proliferation was suppressed by inhibiting expression of NOTUM. Knockdown of NOTUM genes inhibited proliferation as well as migration, with possible involvement of p38 and c-JUN N-terminal kinase in this process. The result was verified in patients with CRC. Conclusion: NOTUM may be a new candidate for diagnostics and therapy of CRC. Colorectal cancer (CRC) is the fourth most common malignancy and a leading cause of cancer-related mortality worldwide (1). Recent estimates suggest that the burden of CRC is expected to increase by 60% by 2030, with more than 2.2 million new cases and 1.1 million deaths (2). A large proportion of this burden could be prevented either by the screening and detection of this cancer at early stages when chances of a cure are substantially higher than at later stages, or by the detection and removal of precancerous lesions (3, 4). Nevertheless, primary screening faces limitations in terms of invasiveness, available capacities, costs, inconvenience, and adherence (5, 6). Although blood-based protein biomarkers such as carcinoembryonic antigen and carbohydrate antigen 19-9 are already utilized in the clinical setting, they cannot be used alone to screen or diagnose cancer because levels of these markers can be abnormal for reasons other than cancer, such as hepatitis and inflammatory bowel disease (7). Thus, there is an urgent need for new biomarkers and molecular targets with relatively high sensitivity and specificity to CRC. Solid tumors such as CRC are composed of malignant cells along with other stromal cells such as neoplastic, mesenchymal, and inflammatory cells (8). Cancer cells interact with other cells through secreted factors, orchestrating complex signaling pathways (9). Cancer cells secrete various factors including soluble factors and proteases that alter adjacent stromal cells toward a permissive and supportive microenvironment for tumor progression (10). This cancer 'secretome' has been receiving increased interest for the discovery of diagnostic or prognostic cancer biomarkers, and can be a good tool for elucidating cancer biology (11, 12). Therefore, a comprehensive analysis of the cancer secretome can lead to discovery of potential biomarkers or therapeutic targets a...

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NOTUM is a potential pharmacodynamic biomarker of Wnt pathway inhibition

Cited by 21 publications

References 20 publications

PORCN inhibition synergizes with PI3K/mTOR inhibition in Wnt-addicted cancers

PORCN inhibition synergizes with PI3K/mTOR inhibition in Wnt-addicted cancers

From top to bottom: Cell polarity in Hedgehog and Wnt trafficking

NOTUM Is Involved in the Progression of Colorectal Cancer

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