Abstract

Patients with metastatic triple-negative breast cancer (TNBC) have a poor prognosis. New approaches for the treatment of TNBC are needed to improve patient survival. The concept of synthetic lethality, brought about by inactivating complementary DNA repair pathways, has been proposed as a promising therapeutic option for these tumors. The TNBC tumor type has been associated with BRCA mutations, and inhibitors of Poly (ADP-ribose) polymerase (PARP), a family of proteins that facilitates DNA repair, have been shown to effectively kill BRCA defective tumors by preventing cells from repairing DNA damage, leading to a loss of cell viability and clonogenic survival. Here we present preclinical efficacy results of combining the PARP inhibitor, ABT-888, with CPT-11, a topoisomerase I inhibitor. CPT-11 binds to topoisomerase I at the replication fork, creating a bulky adduct that is recognized as damaged DNA. When DNA damage was stimulated with CPT-11, protein expression of the nucleotide excision repair enzyme ERCC1 inversely correlated with cell viability, but not clonogenic survival. However, 4 out of the 6 TNBC cells were synergistically responsive by cell viability and 5 out of the 6 TNBC cells were synergistically responsive by clonogenic survival to the combination of ABT-888 and CPT-11. In vivo, the BRCA mutant cell line MX-1 treated with CPT-11 alone demonstrated significant decreased tumor growth; this decrease was enhanced further with the addition of ABT-888. Decrease in tumor growth correlated with an increase in double strand DNA breaks as measured by γ-H2AX phosphorylation. In summary, inhibiting two arms of the DNA repair pathway simultaneously in TNBC cell lines, independent of BRCA mutation status, resulted in un-repairable DNA damage and subsequent cell death.

Highlights

  • Triple-negative breast cancers (TNBCs) fall into the basal breast cancer subtype and lack estrogen receptor (ER), progesterone receptor (PR), and HER2 expression and activation [1]

  • Using six TNBC cell lines, four of which contained BRCA mutations, we found similar to published results using the Poly (ADP-ribose) polymerase (PARP) inhibitor ABT-888

  • We have found that TNBCs with BRCA mutations have enhanced sensitivity to PARP inhibitors, in our experiments using ABT-888

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Summary

Introduction

Triple-negative breast cancers (TNBCs) fall into the basal breast cancer subtype and lack estrogen receptor (ER), progesterone receptor (PR), and HER2 expression and activation [1]. While estrogen and HER2 targeting molecules have improved survival rates for luminal and HER2 breast cancer subtypes, significant advancement in targeted therapy for TNBC has yet to be demonstrated [2]. The BRCA family of genes are tumor suppressors. When mutated, these genes are associated with familial breast and ovarian cancer. It has been predicted that sporadic breast cancers may contain alterations in BRCA genes [5]. In an evaluation of 360 sporadic breast cancers, 80 tumors had BRCA mutations [5]. 54% of these 80 tumors were TNBCs, suggesting a high prevalence of sporadic BRCA mutations in TNBC [5]. Changes in clinical guidelines suggest that women with TNBC under the age of 60 be screened for BRCA mutations [6]

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