Discovering the anti-cancer potential of non-oncology drugs by systematic viability profiling

  • Nat Cancer. 2020 Feb;1(2):235-248. doi: 10.1038/s43018-019-0018-6.
Steven M Corsello  1  2  3 ,  Rohith T Nagari  1 ,  Ryan D Spangler  1 ,  Jordan Rossen  1 ,  Mustafa Kocak  1 ,  Jordan G Bryan  1  4 ,  Ranad Humeidi  1 ,  David Peck  1 ,  Xiaoyun Wu  1 ,  Andrew A Tang  1 ,  Vickie M Wang  1 ,  Samantha A Bender  1 ,  Evan Lemire  1 ,  Rajiv Narayan  1 ,  Philip Montgomery  1 ,  Uri Ben-David  1  5 ,  Colin W Garvie  1 ,  Yejia Chen  1 ,  Matthew G Rees  1 ,  Nicholas J Lyons  1 ,  James M McFarland  1 ,  Bang T Wong  1 ,  Li Wang  1  6 ,  Nancy Dumont  1 ,  Patrick J O'Hearn  1  7 ,  Eric Stefan  1  8 ,  John G Doench  1 ,  Caitlin N Harrington  1 ,  Heidi Greulich  1 ,  Matthew Meyerson  1  2  3 ,  Francisca Vazquez  1 ,  Aravind Subramanian  1 ,  Jennifer A Roth  1 ,  Joshua A Bittker  1  9 ,  Jesse S Boehm  1 ,  Christopher C Mader  1  10 ,  Aviad Tsherniak  1 ,  Todd R Golub  11  12  13  14
Affiliations
  • 1. Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 2. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 3. Harvard Medical School, Boston, MA, USA.
  • 4. Duke University, Durham, NC, USA.
  • 5. Department of Human Molecular Genetics and Biochemistry, Tel Aviv University, Tel Aviv, Israel.
  • 6. 10x Genomics, Pleasanton, CA, USA.
  • 7. Relay Therapeutics, Cambridge, MA, USA.
  • 8. Biogen, Cambridge, MA, USA.
  • 9. Vertex Pharmaceuticals, Boston, MA, USA.
  • 10. Flatiron Health, New York, NY, USA.
  • 11. Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected].
  • 12. Harvard Medical School, Boston, MA, USA. [email protected].
  • 13. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
  • 14. Howard Hughes Medical Institute, Chevy Chase, MD, USA. [email protected].
PMID: 32613204 DOI: 10.1038/s43018-019-0018-6
Abstract

Anti-cancer uses of non-oncology drugs have occasionally been found, but such discoveries have been serendipitous. We sought to create a public resource containing the growth inhibitory activity of 4,518 drugs tested across 578 human Cancer cell lines. We used PRISM, a molecular barcoding method, to screen drugs against cell lines in pools. An unexpectedly large number of non-oncology drugs selectively inhibited subsets of Cancer cell lines in a manner predictable from the cell lines' molecular features. Our findings include compounds that killed by inducing PDE3A-SLFN12 complex formation; vanadium-containing compounds whose killing depended on the sulfate transporter SLC26A2; the alcohol dependence drug disulfiram, which killed cells with low expression of metallothioneins; and the anti-inflammatory drug tepoxalin, which killed via the multi-drug resistance protein ABCB1. The PRISM drug repurposing resource (https://depmap.org/repurposing) is a starting point to develop new oncology therapeutics, and more rarely, for potential direct clinical translation.

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