ATM and MET kinases are synthetic lethal with nongenotoxic activation of p53.
The p53 tumor suppressor orchestrates alternative stress responses including cell cycle arrest and apoptosis, but the mechanisms defining cell fate upon p53 activation are poorly understood. Several small-molecule activators of p53 have been developed, including Nutlin-3, but their therapeutic potential is limited by the fact that they induce reversible cell cycle arrest in most cancer cell types. We report here the results of a genome-wide short hairpin RNA screen for genes that are lethal in combination with p53 activation by Nutlin-3, which showed that the ATM and MET kinases govern cell fate choice upon p53 activation. Genetic or pharmacological interference with ATM or MET activity converts the cellular response from cell cycle arrest into apoptosis in diverse cancer cell types without affecting expression of key p53 target genes. ATM and MET inhibitors also enable Nutlin-3 to kill tumor spheroids. These results identify new pathways controlling the cellular response to p53 activation and aid in the design of p53-based therapies.
Howard Hughes Medical Institute, University of Colorado at Boulder, Boulder, Colorado, USA.
Kelly D
KD
Sullivan
Nuria
N
Padilla-Just
Ryan E
RE
Henry
Christopher C
CC
Porter
Jihye
J
Kim
John J
JJ
Tentler
S Gail
SG
Eckhardt
Aik Choon
AC
Tan
James
J
DeGregori
Joaquín M
JM
Espinosa
D017209:Apoptosis / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005804:Genes, Lethal; D005813:Genes, Synthetic; D016158:Genes, p53; D006801:Humans; D007093:Imidazoles / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D007093:Imidazoles; D010879:Piperazines; D025521:Tumor Suppressor Proteins; C482205:nutlin 3; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases