Exploiting the DNA Repair Defect in BRCA Mutant Cells in the Design of New Therapeutic Strategies for Cancer

Abstract

139Individuals harboring germ-line mutations in the BRCA1 or BRCA2 genes are at highly elevated risk of a variety of cancers. Ten years of research has revealed roles for BRCA1 and BRCA2 in a wide variety of cellular processes. However, it seems likely that the function of these proteins in DNA repair is critically important in maintaining genome stability. Despite this increasing knowledge of the defects present in BRCA-deficient cells, BRCA mutation carriers developing cancer are still treated similarly to sporadic cases. Here we describe our efforts, based on understanding the DNA repair defects in BRCAdeficient cells, to define the optimal existing treatment for cancers arising in BRCA mutation carriers and, additionally, the development of novel therapeutic approaches. Finally, we discuss how therapies developed to treat BRCA mutant tumors might be applied to some sporadic cancers sharing similar specific defects in DNA repair.

DNA Repair, Cancer and Cancer Therapy

“…Inhibition of this protein leads to severe and highly selective toxicity in BRCA-deficient cells. Similar results were obtained on xenografts and in animal models of spontaneous BRCA2 loss of function Farmer et al, 2005;Hay et al, 2005). PARP inhibitors have been previously used as chemosensitizing and radiosensitizing agents.…”

“…This provides an ideal target for therapeutic intervention. Based on the concept that a lethal synthetic interaction between two genes occurs when mutation of either alone is compatible with viability, but mutation of both leads to cell death (Hartwell, 1997;Kaelin, 2005), a DNA repair protein, poly(ADP-ribose) polymerase (PARP), was identified as a synthetic lethal partner of BRCA1 and BRCA2 Farmer et al, 2005). Inhibition of this protein leads to severe and highly selective toxicity in BRCA-deficient cells.…”

Targeting Tankyrase 1 as a therapeutic strategy for BRCA-associated cancer

“…RHS1703; Open Biosystems, Huntsville, AL, USA). Tankyrasesilenced cells (HCT116-Tankyrase 1 shRNA) and control cells (HCT116-Control shRNA) were subsequently transfected with pSUPER shRNA constructs targeting either BRCA1 or BRCA2 (Figure 1b; Tutt et al, 2005;McCabe et al, 2006) and clonogenic survival assays were performed. Our results showed that inhibition of Tankyrase 1 was selectively lethal in cells with a reduction in either BRCA1 or BRCA2 expression, but had no effect in control cells (Figure 1c).…”

Targeting Poly(ADP-Ribose) Polymerase: A Two-Armed Strategy for Cancer Therapy

“…Should these studies confi rm signifi cant activity in the metastatic setting in these familial cancers, it could be postulated that intermittent use of a PARP inhibitor at an early "preventative" stage could eliminate cells with a biallelic loss of BRCA function before they develop into tumors. It is also becoming clear that a wider group of patients may benefi t because a signifi cant number of tumors have a BRCA-like phenotype due to promoter methylation or loss of other elements of the DSB repair pathway (36,52,53).…”