Synthetic Lethality Exploitation by an Anti-Trop-2-SN-38 Antibody-Drug Conjugate, IMMU-132, Plus PARP Inhibitors in BRCA1/2-wild-type Triple-Negative Breast Cancer

Clin Cancer Res. 2017 Jul 1;23(13):3405-3415. doi: 10.1158/1078-0432.CCR-16-2401. Epub 2017 Jan 9.

Abstract

Purpose: Both PARP inhibitors (PARPi) and sacituzumab govitecan (IMMU-132) are currently under clinical evaluation in triple-negative breast cancer (TNBC). We sought to investigate the combined DNA-damaging effects of the topoisomerase I (Topo I)-inhibitory activity of IMMU-132 with PARPi disruption of DNA repair in TNBC.Experimental Design:In vitro, human TNBC cell lines were incubated with IMMU-132 and various PARPi (olaparib, rucaparib, or talazoparib) to determine the effect on growth, double-stranded DNA (dsDNA) breaks, and cell-cycle arrest. Mice bearing BRCA1/2-mutated or -wild-type human TNBC tumor xenografts were treated with the combination of IMMU-132 and PARPi (olaparib or talazoparib). Study survival endpoint was tumor progression to >1.0 cm3 and tolerability assessed by hematologic changes.Results: Combining IMMU-132 in TNBC with all three different PARPi results in synergistic growth inhibition, increased dsDNA breaks, and accumulation of cells in the S-phase of the cell cycle, regardless of BRCA1/2 status. A combination of IMMU-132 plus olaparib or talazoparib produces significantly improved antitumor effects and delay in time-to-tumor progression compared with monotherapy in mice bearing BRCA1/2-mutated HCC1806 TNBC tumors. Furthermore, in mice bearing BRCA1/2-wild-type tumors (MDA-MB-468 or MDA-MB-231), the combination of IMMU-132 plus olaparib imparts a significant antitumor effect and survival benefit above that achieved with monotherapy. Most importantly, this combination was well tolerated, with no substantial changes in hematologic parameters.Conclusions: These data demonstrate the added benefit of combining Topo I inhibition mediated by IMMU-132 with synthetic lethality provided by PARPi in TNBC, regardless of BRCA1/2 status, thus supporting the rationale for such a combination clinically. Clin Cancer Res; 23(13); 3405-15. ©2017 AACR.

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage*
  • Antineoplastic Combined Chemotherapy Protocols / immunology
  • BRCA1 Protein / genetics*
  • BRCA2 Protein / genetics*
  • Camptothecin / administration & dosage
  • Camptothecin / analogs & derivatives*
  • Cell Line, Tumor
  • DNA Repair / drug effects
  • DNA Topoisomerases, Type I / drug effects
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunoconjugates / administration & dosage*
  • Immunoconjugates / immunology
  • Indoles / administration & dosage
  • Mice
  • Phthalazines / administration & dosage
  • Piperazines / administration & dosage
  • Poly(ADP-ribose) Polymerase Inhibitors / administration & dosage
  • Synthetic Lethal Mutations / genetics
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / immunology
  • Triple Negative Breast Neoplasms / pathology
  • Triple Negative Breast Neoplasms / therapy*
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Monoclonal, Humanized
  • BRCA1 Protein
  • BRCA1 protein, human
  • BRCA2 Protein
  • BRCA2 protein, human
  • Immunoconjugates
  • Indoles
  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • rucaparib
  • talazoparib
  • DNA Topoisomerases, Type I
  • sacituzumab govitecan
  • olaparib
  • Camptothecin