Premium
Identification of FZD5 as Genetic Vulnerability in RNF43 Mutant Cancer
Author(s) -
Steinhart Zachary,
Pavlovic Zvezdan,
Chandrashekhar Megha,
Mascall Keith,
Hart Traver,
Wang Xiaowei,
Zhang Xiaoyu,
Brown Kevin R.,
Adams Jarrett,
Pan James,
Sidhu Sachdev,
Moffat Jason,
Angers Stephane
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.804.31
Subject(s) - wnt signaling pathway , biology , mutant , frizzled , cancer research , cancer , gene , genetics
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and novel effective treatments are greatly needed. Recent research revealed that a subset of PDAC cell lines is dependent on the Wnt cell‐signaling pathway for cell proliferation and survival. Wnt‐dependent PDAC all contain mutations in the gene encoding RNF43 . RNF43 acts as a negative regulator of the Wnt pathway through ubiquitination and degradation of the Frizzled (FZD) family of Wnt receptors. RNF43 mutation status may therefore serve as a suitable biomarker for targeted therapy against the Wnt pathway in PDAC. In order to find novel genetic vulnerabilities in RNF43 mutant PDAC, we used genome‐wide CRISPR/Cas9 knockout screens in RNF43 mutant and wild‐type PDAC cell lines. Comparison of essential genes between RNF43 mutant and wild‐type groups was used to find context‐dependent essential genes for the RNF43 mutant genotype. This revealed the unexpected unique requirement of FZD5 (one of ten FZD homologs in humans) as a common genetic vulnerability in RNF43 mutant PDAC lines. This finding was validated through cell proliferation assays in vitro in both established cell lines and a primary patient derived cell line containing RNF43 mutation. Monoclonal antibodies derived against FZD5 were found to be remarkably effective as a single agent therapy both in vitro and in vivo, in subcutaneous and orthotopic xenograft models . Anti‐FZD5 biologics represent a novel potential targeted therapy in RNF43 mutant pancreatic cancers. Support or Funding Information This work was supported from grants funded by the Canadian Institutes for Health Research to S.A. (CIHR‐273548) and J.M. (CIHR‐342551) and by the Ontario Research Fund to S.S. J.M. holds a Canada Research Chair in Functional Genomics of Cancer and S.A. holds a Canada Research Chair in Functional Architecture of Signal Transduction. Z.S. is supported by a scholarship from the Centre for Pharmaceutical Oncology at the Leslie Dan Faculty of Pharmacy, University of Toronto. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .