The nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) represents an important novel target in cancer therapy. It is essential for the repair of single-strand DNA breaks via the base excision repair pathway. Inhibitors of PARP-1 were first developed as chemosensitizers . However, preclinical data suggest that PARP inhibitors can act as single agents to selectively kill cancers with BRCA 1 or 2 mutations and cancers harbouring defects in other DNA repair proteins.
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. PTEN loss of function is the most common genetic aberration in endometrioid endometrial carcinomas. In addition to its well-described role in cell signaling, PTEN is involved in the maintenance of genomic stability . Loss of PTEN function causes defects in repair of DNA double-strand breaks by homologous recombination and, therefore, sensitizes cells to inhibition of the poly(adenosine diphosphate ribose) polymerase (PARP). PTEN deficiency causes a homologous recombination 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[1].
In the recent study, which is about PTEN and PARP inhibitor , PTEN-deficient cells showed a significantly greater sensitivity to KU0058948 than the two endometrioid endometrial carcinoma cell lines with wild-type PTEN. The cell lines lacking PTEN expression were unable to elicit a homologous recombination damage response as assayed by RAD51 focus function upon irradiation and treatment with PARP inhibitors[2].
ABT-888 , as well as Olaparib, is a good potent PARP inhibitor, maybe it could be used in PTEN study.
References
[1] Ana M. Mendes-Pereira,et al. EMBO Molecular Medicine ,Volume 1, Issue 6-7, pages 315–322, September/October 2009
[2] Konstantin J. Dedes,et al. Sci Transl Med 13 October 2010: Vol. 2, Issue 53, p. 53ra75
