Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells.
We used synthetic lethal high-throughput screening to interrogate 23,550 compounds for their ability to kill engineered tumorigenic cells but not their isogenic normal cell counterparts. We identified known and novel compounds with genotype-selective activity, including doxorubicin, daunorubicin, mitoxantrone, camptothecin, sangivamycin, echinomycin, bouvardin, NSC146109, and a novel compound that we named erastin. These compounds have increased activity in the presence of hTERT, the SV40 large and small T oncoproteins, the human papillomavirus type 16 (HPV) E6 and E7 oncoproteins, and oncogenic HRAS. We found that overexpressing hTERT and either E7 or LT increased expression of topoisomerase 2alpha and that overexpressing RAS(V12) and ST both increased expression of topoisomerase 1 and sensitized cells to a nonapoptotic cell death process initiated by erastin.
Dolma
Sonam
S
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
Lessnick
Stephen L
SL
Hahn
William C
WC
Stockwell
Brent R
BR
D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death; D002460:Cell Line; D002472:Cell Transformation, Viral; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000187:drug effects; D005452:Fluoresceins / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005818:Genetic Engineering; D005838:Genotype; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D015513:Oncogene Proteins / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D012190:Retroviridae / Q000235:genetics; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D005452:Fluoresceins; D005456:Fluorescent Dyes; D015513:Oncogene Proteins; D010879:Piperazines; C477224:erastin; C085925:calcein AM