Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors.
The tumour suppressor gene, phosphatase and tensin homolog (PTEN), is one of the most commonly mutated genes in human cancers. Recent evidence suggests that PTEN is important for the maintenance of genome stability. Here, we show that PTEN deficiency causes a homologous recombination (HR) defect in human tumour cells. The HR deficiency caused by PTEN deficiency, sensitizes tumour cells to potent inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP), both in vitro and in vivo. PARP inhibitors are now showing considerable promise in the clinic, specifically in patients with mutations in either of the breast cancer susceptibility genes BRCA1 or BRCA2. The data we present here now suggests that the clinical assessment of PARP inhibitors should be extended beyond those with BRCA mutations to a larger group of patients with PTEN mutant tumours.
Mendes-Pereira
Ana M
AM
The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
Martin
Sarah A
SA
Brough
Rachel
R
McCarthy
Afshan
A
Taylor
Jessica R
JR
Kim
Jung-Sik
JS
Waldman
Todd
T
Lord
Christopher J
CJ
Ashworth
Alan
A
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy*; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D010793:Phthalazines / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011995:Recombination, Genetic / Q000187:drug effects
D000964:Antimetabolites, Antineoplastic; D019313:BRCA1 Protein; D024682:BRCA2 Protein; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C531550:olaparib