In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer

Michiko Kodama, Takahiro Kodama, Justin Y. Newberg, Hiroyuki Katayama, Makoto Kobayashi, Samir M. Hanash, Kosuke Yoshihara, Zhubo Wei, Jean C. Tien, Roberto Rangel, Kae Hashimoto, Seiji Mabuchi, Kenjiro Sawada, Tadashi Kimura, Neal G. Copeland, Nancy A. Jenkins

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Epithelial ovarian cancer (EOC) is a deadly cancer, and its prognosis has not been changed significantly during several decades. To seek new therapeutic targets for EOC, we performed an in vivo dropout screen in human tumor xenografts using a pooled shRNA library targeting thousands of druggable genes. Then, in follow-up studies, we performed a second screen using a genome-wide CRISPR/Cas9 library. These screens identified 10 high-confidence drug targets that included well-known oncogenes such as ERBB2 and RAF1, and novel oncogenes, notably KPNB1, which we investigated further. Genetic and pharmacological inhibition showed that KPNB1 exerts its antitumor effects through multiphase cell cycle arrest and apoptosis induction. Mechanistically, proteomic studies revealed that KPNB1 acts as a master regulator of cell cycle-related proteins, including p21, p27, and APC/ C. Clinically, EOC patients with higher expression levels of KPNB1 showed earlier recurrence and worse prognosis than those with lower expression levels of KPNB1. Interestingly, ivermectin, a Food and Drug Administration-approved antiparasitic drug, showed KPNB1-dependent antitumor effects on EOC, serving as an alternative therapeutic toward EOC patients through drug repositioning. Last, we found that the combination of ivermectin and paclitaxel produces a stronger antitumor effect on EOC both in vitro and in vivo than either drug alone. Our studies have thus identified a combinatorial therapy for EOC, in addition to a plethora of potential drug targets.

Original languageEnglish (US)
Pages (from-to)E7301-E7310
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number35
DOIs
StatePublished - Aug 29 2017

Keywords

  • CRISPR/Cas
  • KPNB1
  • Loss-of-function screen
  • Ovarian cancer
  • RNAi

ASJC Scopus subject areas

  • General

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