title: Protein expression of DNA damage repair proteins dictates response to topoisomerase and PARP inhibitors in triple-negative breast cancer.
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.
authors.affiliation: Department of Oncology, Wayne State University, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, United States of America.
authors.forename: Julie L
authors.initials: JL
authors.lastname: Boerner
authors.affiliation: Department of Oncology, Wayne State University, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, United States of America.
authors.forename: Nicole
authors.initials: N
authors.lastname: Nechiporchik
authors.affiliation: Department of Oncology, Wayne State University, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, United States of America.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Mueller
authors.affiliation: Department of Oncology, Wayne State University, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, United States of America.
authors.forename: Lisa
authors.initials: L
authors.lastname: Polin
authors.affiliation: Department of Oncology, Wayne State University, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, United States of America.
authors.forename: Lance
authors.initials: L
authors.lastname: Heilbrun
authors.affiliation: Department of Oncology, Wayne State University, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, United States of America; Department of Oncology, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Boerner
authors.affiliation: Department of Oncology, Wayne State University, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, United States of America.
authors.forename: Gina L
authors.initials: GL
authors.lastname: Zoratti
authors.affiliation: Department of Oncology, Wayne State University, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, United States of America.
authors.forename: Karri
authors.initials: K
authors.lastname: Stark
authors.affiliation: Department of Oncology, Wayne State University, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, United States of America; Department of Oncology, Yale University, New Haven, Connecticut, United States of America.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: LoRusso
authors.affiliation: Department of Oncology, Wayne State University, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, United States of America.
authors.forename: Angelika
authors.initials: A
authors.lastname: Burger
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000494:pharmacology; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004357:Drug Synergism; D004720:Endonucleases / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D001562:Benzimidazoles; D004268:DNA-Binding Proteins; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D059004:Topoisomerase I Inhibitors; C521013:veliparib; D000077146:Irinotecan; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C071447:ERCC1 protein, human; D004720:Endonucleases; D002166:Camptothecin