Chemical genomics with pyrvinium identifies C1orf115 as a regulator of drug efflux

Nat Chem Biol. 2022 Dec;18(12):1370-1379. doi: 10.1038/s41589-022-01109-0.

Sanna N Masud ^# ¹ ² ³, Megha Chandrashekhar ^# ¹ ² ⁴, Michael Aregger ² ⁵, Guihong Tan ², Xiaoyu Zhang ², Patricia Mero ² ³, David A Pirman ³, Olga Zaslaver ², Gromoslaw A Smolen ⁶ ⁷, Zhen-Yuan Lin ⁸, Cassandra J Wong ⁸, Charles Boone ¹ ², Anne-Claude Gingras ¹ ⁸, J Rafael Montenegro-Burke ¹ ², Jason Moffat ⁹ ¹⁰ ¹¹ ¹²

Affiliations

1 Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
2 Donnelly Centre, Toronto, ON, Canada.
3 Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
4 Canadian Nuclear Laboratories, Chalk River, ON, Canada.
5 Center for Cancer Research, National Cancer Institute, Frederick, MD, USA.
6 Agios Pharmaceuticals, Cambridge, MA, USA.
7 Celsius Therapeutics, Cambridge, MA, USA.
8 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
9 Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. jason.moffat@sickkids.ca.
10 Donnelly Centre, Toronto, ON, Canada. jason.moffat@sickkids.ca.
11 Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada. jason.moffat@sickkids.ca.
12 Institute for Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada. jason.moffat@sickkids.ca.
# Contributed equally.

PMID: 35970996 DOI: 10.1038/s41589-022-01109-0

Abstract

Pyrvinium is a quinoline-derived cyanine dye and an approved anti-helminthic drug reported to inhibit Wnt signaling and have anti-proliferative effects in various Cancer cell lines. To further understand the mechanism by which pyrvinium is cytotoxic, we conducted a pooled genome-wide CRISPR loss-of-function screen in the human HAP1 cell model. The top drug-gene sensitizer interactions implicated the malate-aspartate and glycerol-3-phosphate shuttles as mediators of cytotoxicity to mitochondrial complex I inhibition including pyrvinium. By contrast, perturbation of the poorly characterized gene C1orf115/RDD1 resulted in strong resistance to the cytotoxic effects of pyrvinium through dysregulation of the major drug efflux pump ABCB1/MDR1. Interestingly, C1orf115/RDD1 was found to physically associate with ABCB1/MDR1 through proximity-labeling experiments and perturbation of C1orf115 led to mis-localization of ABCB1/MDR1. Our results are consistent with a model whereby C1orf115 modulates drug efflux through regulation of the major drug exporter ABCB1/MDR1.

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