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Proc Natl Acad Sci U S A. 2017 Aug 29;114(35):E7301-E7310. doi: 10.1073/pnas.1705441114. Epub 2017 Aug 15.

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

Author information

1
Cancer Research Program, Houston Methodist Research Institute, Houston, TX 77030.
2
Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka 5650871, Japan.
3
Cancer Research Program, Houston Methodist Research Institute, Houston, TX 77030; t-kodama@gh.med.osaka-u.ac.jp njenkins1@mdanderson.org.
4
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Osaka 5650871, Japan.
5
Department of Molecular Oncology, Moffitt Cancer Center, Tampa, FL 33612.
6
Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
7
Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 9518510, Japan.
8
Department of Pathology, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109.
9
Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
10
Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, TX 77030.

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.

KEYWORDS:

CRISPR/Cas; KPNB1; RNAi; loss-of-function screen; ovarian cancer

PMID:
28811376
PMCID:
PMC5584430
DOI:
10.1073/pnas.1705441114
[Indexed for MEDLINE]
Free PMC Article

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