Content area
Full Text
The paper explained
PROBLEM:
The tumour suppressor gene, PTEN, is one of the most commonly mutated genes in human cancers. Selectively targeting cancerous PTEN deficient cells would likely make for an efficient and relatively safe cancer therapy applicable to the large number of PTEN deficient cancers. Selective targeting of BRCA1 or BRCA2 deficient tumours has recently been demonstrated with Olaparib, a high‐potency PARP inhibitor. This drug can elicit sustained responses in BRCA deficient cancers without causing some of the negative side effects caused by standard chemotherapies. Tumour cells in BRCA mutant patients have a defect in the DNA repair process of HR that repairs DSBs and it is thought that PARP inhibitors target this HR defect by increasing the formation of DSBs.
RESULTS:
Recent evidence suggests that, like BRCA mutant cells, PTEN mutant cells are also characterized by an increase in DSBs, suggesting that drugs that target BRCA mutation could also be used to target PTEN mutation. We demonstrate that PTEN deficiency in human tumour cells also leads to suppression of HR. Using in vitro cell culture and in vivo tumour modelling in mice, we show that, as in BRCA deficient tumours, the HR deficiency in PTEN mutant cells can be exploited therapeutically by Olaparib.
IMPACT:
Our work suggests that this relatively non‐toxic anti‐cancer drug can be used to target the large number of PTEN deficient tumours, significantly extending its previously anticipated limited spectrum.
INTRODUCTION
Synthetic lethal approaches to cancer treatment have the potential to deliver relatively large therapeutic windows and significant patient benefit (Kaelin, 2005). We, and others, have previously shown that mutations in either of the tumour suppressor genes, breast cancer 1 (BRCA1) or BRCA2, are synthetically lethal with inhibition of the DNA repair enzyme poly(ADP‐ribose) polymerase 1 (PARP1) (Bryant et al, 2005; Farmer et al, 2005). The exquisite sensitivity of BRCA1 or BRCA2 mutant cells to PARP inhibitors (PARPi) forms the rationale behind clinical trials that are now assessing the potential of these agents (Ashworth, 2008). The preliminary results from these clinical trials are promising, with favourable toxicity and sustained tumour responses to the drug (Fong et al, 2009).
Mutations in the phosphatase and tensin homolog (PTEN) gene (OMIM 601728) and...