Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors

Abstract

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.

Nuclear PTEN tumor-suppressor functions through maintaining heterochromatin structure

“…27 In agreement, we determined that WT PTEN cells displayed decreased sensitivity to the PARP inhibitor, BMN673. However, similar sensitivity to BMN673 was observed in control and both PTEN Y336* and PTEN-HP1aKD mutant reconstituted BT-549 cells (Fig.…”

Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial

“…Progression-free survival was signifi cantly longer in the BRCA mutant subgroup (HR 0·27, 95% CI 0·16-0·44, p<0·0001) and LOH high subgroup (HR 0·62, 0·42-0·90, p=0·011) than in the LOH low subgroup (fi gure 2A). 12 month progressionfree survival was higher in the BRCA mutant subgroup (50%, 95% CI 33-65) and LOH high subgroup (28%, 18-39) than in the LOH low subgroup (10%, [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. The proportionality of hazards assumption was not violated (appendix pp [4][5]15).…”

“…Formalin-fi xed paraffi n-embedded archival and pretreatment tumour biopsies of adequate quality were required for each patient. A complete list of inclusion and exclusion criteria is provided in the appendix (pp [16][17].…”

CTEN (C-terminal tensin-like), a novel oncogene overexpressed in invasive breast carcinoma of poor prognosis

“…Worldwide, more than one million new cases of BC are diagnosed annually. In the UK, BC is now the most common cancer and almost 46,000 new cases are diagnosed every year [2].…”