Hélène Marijon1, Dhong Hyun Lee2, LingWen Ding3, Haibo Sun2, Sigal Gery2, Aimery de Gramont4, H Phillip Koeffler5. 1. Division of Hematology and Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, United States; Oncology Department, Franco-British Institute, Paris, France. Electronic address: helene.marijon@ihfb.org. 2. Division of Hematology and Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, United States. 3. National Cancer Institute and Cancer Science Institute, National University of Singapore, Singapore. 4. Oncology Department, Franco-British Institute, Paris, France. 5. Division of Hematology and Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA, United States; National Cancer Institute and Cancer Science Institute, National University of Singapore, Singapore.
Abstract
PURPOSE: Despite similarities with BRCA-mutated breast cancers, triple-negative breast cancers (TNBC) remain resistant to poly(ADP-ribose) polymerase (PARP) inhibitors as single agents. Histone deacetylase inhibitors (HDACi) can decrease expression of proteins involved in DNA repair. We thus hypothesized that a HDACi (suberoylanilide hydroxamic acid (SAHA) or belinostat) could sensitize TNBC to the PARP inhibitor olaparib. METHODS: Human TNBC cells were co-treated with olaparib and either SAHA or belinostat, and their effects on survival, proliferation, cell cycle, apoptosis and DNA repair pathways were evaluated. Subcutaneous xenografts were used to determine the effect of the combination treatment in vivo. RESULTS: HDACi and olaparib synergistically inhibited proliferation of a panel of 8 TNBC cell lines in vitro and in nude mice harboring TNBC xenografts in vivo. We noted a weaker synergism in PTEN-deficient TNBC cells and a stronger synergism in BRCA1-mutated TNBC cells. In the BRCA1-mutated cell line HCC-1937, we observed a drastic decrease in the expression of proteins involved in homologous recombination (HR), leading to a large imbalance of the ratio P-H2AX/RAD51. In BRCA1 wild type (wt) cell lines, effect of the combination treatment relied on DNA damage-induced cell cycle arrest followed by induction of apoptosis. CONCLUSION: In summary, these results provide a preclinical rationale to combine a HDACi with a PARP inhibitor to reduce HR efficiency in TNBC and sensitize these aggressive tumors to PARP inhibition.
PURPOSE: Despite similarities with BRCA-mutated breast cancers, triple-negative breast cancers (TNBC) remain resistant to poly(ADP-ribose) polymerase (PARP) inhibitors as single agents. Histone deacetylase inhibitors (HDACi) can decrease expression of proteins involved in DNA repair. We thus hypothesized that a HDACi (suberoylanilide hydroxamic acid (SAHA) or belinostat) could sensitize TNBC to the PARP inhibitor olaparib. METHODS:Human TNBC cells were co-treated with olaparib and either SAHA or belinostat, and their effects on survival, proliferation, cell cycle, apoptosis and DNA repair pathways were evaluated. Subcutaneous xenografts were used to determine the effect of the combination treatment in vivo. RESULTS: HDACi and olaparib synergistically inhibited proliferation of a panel of 8 TNBC cell lines in vitro and in nude mice harboring TNBC xenografts in vivo. We noted a weaker synergism in PTEN-deficient TNBC cells and a stronger synergism in BRCA1-mutated TNBC cells. In the BRCA1-mutated cell line HCC-1937, we observed a drastic decrease in the expression of proteins involved in homologous recombination (HR), leading to a large imbalance of the ratio P-H2AX/RAD51. In BRCA1 wild type (wt) cell lines, effect of the combination treatment relied on DNA damage-induced cell cycle arrest followed by induction of apoptosis. CONCLUSION: In summary, these results provide a preclinical rationale to combine a HDACi with a PARP inhibitor to reduce HR efficiency in TNBC and sensitize these aggressive tumors to PARP inhibition.