Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors

By A. Mendes-Pereira, S. Martin, R. Brough, Afshan Mccarthy, J. R. Taylor, Jung‐Sik Kim, T. Waldman, C. Lord, Alan Ashworth. EMBO Molecular Medicine, 2009

674 citations recorded by the source corpus.

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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/4d377a58e95d7a878eb34eee23191f2bc8ff1465

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Citations in the corpus

Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer (2012, background): “Elevated HRD scores were also seen in PTEN-deficient tumours, consistent with reports that PTEN-defective tumour cell are HR defective (Mendes-Pereira et al, 2009).”
Cancer genomics: from discovery science to personalized medicine (2011, background): “Similarly, DNA sequencing of cancer cell lines and correlations of mutation status with in vitro drug sensitivity have identified loss of PTEN as a potential marker for response to PARP inhibitors that are in clinical developmen”
The DNA damage response and cancer therapy (2012, background): “In addition, mutations in the tumour-suppressor gene PTEN”
Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. (2010, background): “Preclinical data suggest that olaparib may also have significant antitumor activity in sporadic metastatic ovarian, as well as other cancers with HR DNA repair defects,(22) including tumors lacking the tumor suppressor gene PTEN,(23,24) which may confer sensitivity to olaparib.(25) Moreover, HR DNA ”
Strategies to improve radiotherapy with targeted drugs (2011, background): “Recent studies report that tumour-specific loss of PTEN reduces HR capacity, possibly owing to the reduction in expression of RAD51 and its paralogues, suggesting the use of PARP inhibitors in combination with ionizing radiation in such tumour”
Homologous recombination deficiency: Exploiting the fundamental vulnerability of ovarian cancer (2015, background): “PTEN deficiency has been reported to be synthetically lethal with PARP inhibition, and one of the proposed mechanisms is transcriptional downregulation of RAD51 (31, 32).”
PARP inhibition: PARP1 and beyond (2010, background): “For instance, with the recent finding that the tumour suppressor PTEN is important for expression of the repair protein RAD51 , it was shown that PTEN-deficient cells are exquisitely sensitive to PARP inhibitor”
Stereospecific PARP trapping by BMN 673 and comparison with olaparib and rucaparib (2013, background): “One possibility is that sensitive cell lines are deficient in postreplication repair, Fanconi anemia pathway, ATM, homologous recombination (27), or PTEN (49).”