Acquired Resistance to Combination Treatment with Temozolomide and ABT-888 Is Mediated by Both Base Excision Repair and Homologous Recombination DNA Repair Pathways

Abstract

Many established cancer therapies involve DNA-damaging chemotherapy or radiotherapy. Gain of DNA repair capacity of the tumor represents a common mechanism used by cancer cells to survive DNA-damaging therapy. Poly(ADPribose) polymerase-1 (PARP-1) is a nuclear enzyme that is activated by DNA damage and plays a critical role in base excision repair. Inhibition of PARP represents an attractive approach for the treatment of cancer. Previously, we have described the discovery and characterization of a potent PARP inhibitor, ABT-888. ABT-888 potentiates the activity of DNA-damaging agents such as temozolomide (TMZ) in a variety of preclinical models. We report here the generation of HCT116 cells resistant to treatment with TMZ and ABT-888 (HCT116R cells). HCT116R cells exhibit decreased H2AX phosphorylation in response to treatment with TMZ and ABT-888 relative to parental HCT116 cells. Microarray and Western blot studies indicate that HCT116R cells have decreased PARP-1 and elevated Rad51 expression levels. HCT116R cells are dependent on Rad51 for proliferation and survival, as shown by inhibition of proliferation and induction of apoptosis upon treatment with Rad51 small interfering RNA. In addition, HCT116R cells are more resistant to radiation than the parental HCT116 cells. Our study suggests that cancer cells upregulate the homologous recombination DNA repair pathway to compensate for the loss of base excision repair, which may account for the observed resistance to treatment with TMZ and ABT-888.

Enhanced Killing of Cancer Cells by Poly(ADP-ribose) Polymerase Inhibitors and Topoisomerase I Inhibitors Reflects Poisoning of Both Enzymes

“…Studies are currently in progress in a number of laboratories to determine which aspects of repair are modulated by PARP inhibitors (32,64,98,99). Our results along with those of Zhang et al (32) indicate that TDP1 knockdown sensitizes cells to topotecan and abrogates further sensitization by veliparib (supplemental Fig.…”

Sulforaphane reverses chemo-resistance to temozolomide in glioblastoma cells by NF-κB-dependent pathway downregulating MGMT expression

“…GBM is considered as a heterogeneous group of tumors with differing cellular lineages, genetic alteration, biological behavior and response to chemotherapeutics. TMZ resistance in GBM also involves different cellular pathways resulting in large number of gene changes (37,38). Although some of the potential mechanisms have not been revealed, persistent NF-κB activity can be a result of tumor amplification, invasion and chemo-resistance by targeting transcription of various genes involved in immunoregulation, inflammation, growth, carcinogenesis and apoptosis (39).…”

Iniparib Nonselectively Modifies Cysteine-Containing Proteins in Tumor Cells and Is Not a Bona Fide PARP Inhibitor

“…Induction of gH2AX is a widely used measure of DSB formation and we have shown previously that cell cytotoxicity is correlated with the induction of gH2AX signal in HCT116 cells treated with veliparib plus temozolomide (11,32). We used this same approach to monitor the induction of DNA damage in the DLD1 BRCA2 isogenic pair.…”