Dual fluorescence isogenic synthetic lethal kinase screen and high-content secondary screening for MUC16/CA125-selective agents Journal Article


Authors: Rao, T. D.; Xu, M.; Eng, S.; Yang, G.; Manson, R.; Rosales, N.; Kumar, R.; Veillard, I. E.; Zhou, Q.; Iasonos, A.; Ouerfelli, O.; Djaballah, H.; Spriggs, D. R.; Yeku, O. O.
Article Title: Dual fluorescence isogenic synthetic lethal kinase screen and high-content secondary screening for MUC16/CA125-selective agents
Abstract: Significant strides have been made in the development of precision therapeutics for cancer. Aberrantly expressed glycoproteins represent a potential avenue for therapeutic development. The MUC16/CA125 glycoprotein serves as a biomarker of disease and a driver of malignant transformation in epithelial ovarian cancer. Previously, we demonstrated a proof-of-principle approach to selectively targeting MUC16þ cells. In this report, we performed a synthetic lethal kinase screen using a human kinome RNAi library and identified key pathways preferentially targetable in MUC16þ cells using isogenic dual-fluorescence ovarian cancer cell lines. Using a separate approach, we performed high-content small-molecule screening of six different libraries of 356,982 compounds for MUC16/CA125-selective agents and identified lead candidates that showed preferential cytotoxicity in MUC16þ cells. Compounds with differential activity were selected and tested in various other ovarian cell lines or isogenic pairs to identify lead compounds for structure–activity relationship (SAR) selection. Lead siRNA and small-molecule inhibitor candidates preferentially inhibited invasion of MUC16þ cells in vitro and in vivo, and we show that this is due to decreased activation of MAPK, and non–receptor tyrosine kinases. Taken together, we present a comprehensive screening approach to the development of a novel class of MUC16-selective targeted therapeutics and identify candidates suitable for further clinical development. © 2022 American Association for Cancer Research
Keywords: genetics; ovarian neoplasms; metabolism; fluorescence; membrane proteins; pathology; cell line, tumor; ovary tumor; membrane protein; tumor cell line; ca 125 antigen; ca-125 antigen; muc16 protein, human; humans; human; female; carcinoma, ovarian epithelial
Journal Title: Molecular Cancer Therapeutics
Volume: 21
Issue: 5
ISSN: 1535-7163
Publisher: American Association for Cancer Research  
Date Published: 2022-05-01
Start Page: 775
End Page: 785
Language: English
DOI: 10.1158/1535-7163.Mct-21-0572
PUBMED: 35413118
PROVIDER: scopus
PMCID: PMC9081202
DOI/URL:
Notes: Article -- Export Date: 1 June 2022 -- Source: Scopus
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MSK Authors
  1. Dharmarao Thapi
    38 Thapi
  2. Qin Zhou
    255 Zhou
  3. Alexia Elia Iasonos
    365 Iasonos
  4. Ouathek Ouerfelli
    102 Ouerfelli
  5. Guangli Yang
    34 Yang
  6. Hakim Djaballah
    101 Djaballah
  7. David R Spriggs
    325 Spriggs
  8. Nestor S Rosales
    33 Rosales
  9. Stephanie Lauren Eng
    3 Eng
  10. Robin Gayle Manson
    1 Manson