PTEN Loss Compromises Homologous Recombination Repair in Astrocytes: Implications for Glioblastoma Therapy with Temozolomide or Poly(ADP-Ribose) Polymerase Inhibitors

Abstract

Glioblastomas (GBM) are lethal brain tumors that are highly resistant to therapy. The only meaningful improvement in therapeutic response came from use of the S N 1-type alkylating agent temozolomide in combination with ionizing radiation. However, no genetic markers that might predict a better response to DNA alkylating agents have been identified in GBMs, except for loss of O 6-methylguanine-DNA methyltransferase via promoter methylation. In this study, using genetically defined primary murine astrocytes as well as human glioma lines, we show that loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) confers sensitivity to N-methyl-N′-nitro-N-nitrosoguanidine (MNNG), a functional analogue of temozolomide. We find that MNNG induces replication-associated DNA double-strand breaks (DSB), which are inefficiently repaired in PTEN-deficient astrocytes and trigger apoptosis. Mechanistically, this is because PTEN-null astrocytes are compromised in homologous recombination (HR), which is important for the repair of replication-associated DSBs. Our results suggest that reduced levels of Rad51 paralogs in PTEN-null astrocytes might underlie the HR deficiency of these cells. Importantly, the HR deficiency of PTEN-null cells renders them sensitive to the poly (ADP-ribose) polymerase (PARP) inhibitor ABT-888 due to synthetic lethality. In sum, our results tentatively suggest that patients with PTEN-null GBMs (about 36%) may especially benefit from treatment with DNA alkylating agents such as temozolomide. Significantly, our results also provide a rational basis for treating the subgroup of patients who are PTEN deficient with PARP inhibitors in addition to the current treatment regimen of radiation and temozolomide. Cancer Res; 70(13); 5457-64. ©2010 AACR.

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].…”

Quinazolinone derivatives as inhibitors of homologous recombinase RAD51

“…Varying spacer length in compound 17, with one methylene unit shorter (15) or longer (16), did not improve activity and indicated optimal positioning of the aromatic ring in 17. Of the substituted benzyl series, fluoro (18)(19)(20), nitro (21-22) and p-hydroxy (23) analogues showed comparable activity. A polar substrate, such as pacetamidomethyl (24) and carboxylic acid (25-26), were detrimental, while 3,4-dichloro (27) conferred a slight improvement.…”

“…These differing sensitivity profiles to RAD51 inhibition are reflected in the IC 50 values and the corresponding dose-curves (Supporting Information Figure S1). BT549 cells contain a PTEN mutation, which compromises HR activity 20 , reflected by a gentler sloped dose curve in response to RAD51 inhibition. However, RAD51 inhibition was minimally toxic to normal breast epithelial cell line MCF10A which has unperturbed access to both HR and NHEJ repair pathways (IC 50 ~ 48 µM, Table 1), suggesting a promising role in selectively inhibiting aggressive, metastatic breast cancer cells rather than normal cells.…”

Modeling Astrocytoma Pathogenesis <em>In Vitro</em> and <em>In Vivo</em> Using Cortical Astrocytes or Neural Stem Cells from Conditional, Genetically Engineered Mice

“…We and others have developed astrocytoma nGEM using primary cells -astrocytes, NSC, or oligodendrocyte precursor cells (OPC) -harvested from GEM [30][31][32][33][34] . The rationale behind the development of an astrocytoma nGEM was to create a model to determine the phenotypic consequences of oncogenic mutations in specific cell types that could potentially be used for preclinical drug testing in vitro and in vivo in immune-competent animals.…”