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.

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.

• Authors: Thomas M Cardillo, Robert M Sharkey, Diane L Rossi, Roberto Arrojo, Ali A Mostafa, David M Goldenberg
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 23 Issue 13 Pg. 3405-3415 (07 01 2017) ISSN: 1557-3265 [Electronic] United States
• PMID: 28069724 (Publication Type: Journal Article)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• 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

Topics

• Animals
• Antibodies, Monoclonal, Humanized (administration & dosage)
• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, immunology)
• BRCA1 Protein (genetics)
• BRCA2 Protein (genetics)
• Camptothecin (administration & dosage, 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, 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, immunology, pathology, therapy)
• Xenograft Model Antitumor Assays