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. [email protected].
  • 10. Donnelly Centre, Toronto, ON, Canada. [email protected].
  • 11. Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada. [email protected].
  • 12. Institute for Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada. [email protected].
  • # 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.