title: Synthetic Lethal Approaches Exploiting DNA Damage in Aggressive Myeloma.
abstract: Ongoing DNA damage is a common feature of epithelial cancers. Here, we show that tumor cells derived from multiple myeloma, a disease of clonal plasma cells, demonstrate DNA-replicative stress, leading to DNA damage. We identified a poor-prognosis subset of multiple myeloma with extensive chromosomal instability and replicative stress, which rely on ATR to compensate for DNA-replicative stress; conversely, silencing of ATR or treatment with a specific ATR inhibitor triggers multiple myeloma cell apoptosis. We show that oncogenes, such as MYC, induce DNA damage in multiple myeloma cells not only by increased replicative stress, but also via increased oxidative stress, and that reactive oxygen species-inducer piperlongumine triggers further DNA damage and apoptosis. Importantly, ATR inhibition combined with piperlongumine triggers synergistic multiple myeloma cytotoxicity. This synthetic lethal approach, enhancing oxidative stress while concomitantly blocking replicative stress response, provides a novel combination targeted therapy to address an unmet medical need in this subset of multiple myeloma.
  
  
  CONCLUSIONS
  Multiple myeloma remains an incurable disease. We have identified a subset of multiple myeloma patients with poor prognosis, whose tumors present chromosomal instability, replicative and oxidative stress, and DNA damage. We define a synthetic lethal approach enhancing oxidative stress while targeting replicative stress response, inducing tumor cell apoptosis in this patient subset. Cancer Discov; 5(9); 972-87. ©2015 AACR.This article is highlighted in the In This Issue feature, p. 893.
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. Functional Genomics of Cancer Unit, Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cottini
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Rikio
authors.initials: R
authors.lastname: Suzuki
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Tai
authors.affiliation: Department of Medical Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Hospital, Milan, Italy.
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Bianchini
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.affiliation: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts. tonon.giovanni@hsr.it kenneth_anderson@dfci.harvard.edu.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.affiliation: Functional Genomics of Cancer Unit, Division of Experimental Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) San Raffaele Scientific Institute, Milan, Italy. tonon.giovanni@hsr.it kenneth_anderson@dfci.harvard.edu.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tonon
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D043171:Chromosomal Instability; D016000:Cluster Analysis; D004249:DNA Damage / Q000187:drug effects; D004261:DNA Replication; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D018384:Oxidative Stress; D011379:Prognosis; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013450:Sulfones / Q000494:pharmacology
chemical_list: C560580:3-amino-6-(4-(methylsulfonyl)phenyl)-N-phenylpyrazine-2-carboxamide; D000970:Antineoplastic Agents; D000975:Antioxidants; D016271:Proto-Oncogene Proteins c-myc; D011719:Pyrazines; D017382:Reactive Oxygen Species; D013450:Sulfones