title: Synthetic lethality in ATM-deficient RAD50-mutant tumors underlies outlier response to cancer therapy.
abstract: Metastatic solid tumors are almost invariably fatal. Patients with disseminated small-cell cancers have a particularly unfavorable prognosis, with most succumbing to their disease within two years. Here, we report on the genetic and functional analysis of an outlier curative response of a patient with metastatic small-cell cancer to combined checkpoint kinase 1 (CHK1) inhibition and DNA-damaging chemotherapy. Whole-genome sequencing revealed a clonal hemizygous mutation in the Mre11 complex gene RAD50 that attenuated ATM signaling which in the context of CHK1 inhibition contributed, via synthetic lethality, to extreme sensitivity to irinotecan. As Mre11 mutations occur in a diversity of human tumors, the results suggest a tumor-specific combination therapy strategy in which checkpoint inhibition in combination with DNA-damaging chemotherapy is synthetically lethal in tumor cells but not normal cells with somatic mutations that impair Mre11 complex function.
  
  
  CONCLUSIONS
  Strategies to effect deep and lasting responses to cancer therapy in patients with metastatic disease have remained difficult to attain, especially in early-phase clinical trials. Here, we present an in-depth genomic and functional genetic analysis identifying RAD50 hypomorphism as a contributing factor to a curative response to systemic combination therapy in a patient with recurrent, metastatic small-cell cancer.
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Hikmat
authors.initials: H
authors.lastname: Al-Ahmadie
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Gopa
authors.initials: G
authors.lastname: Iyer
authors.affiliation: Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Marcel
authors.initials: M
authors.lastname: Hohl
authors.affiliation: Department of Medicine, University of California, San Francisco, California. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Asthana
authors.affiliation: Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Akiko
authors.initials: A
authors.lastname: Inagaki
authors.affiliation: Computational Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Schultz
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Aphrothiti J
authors.initials: AJ
authors.lastname: Hanrahan
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Sasinya N
authors.initials: SN
authors.lastname: Scott
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: A Rose
authors.initials: AR
authors.lastname: Brannon
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Gregory C
authors.initials: GC
authors.lastname: McDermott
authors.affiliation: Bioinformatics Core Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Mono
authors.initials: M
authors.lastname: Pirun
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Irina
authors.initials: I
authors.lastname: Ostrovnaya
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Philip
authors.initials: P
authors.lastname: Kim
authors.affiliation: Bioinformatics Core Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Socci
authors.affiliation: Genomics Core Laboratory, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Agnes
authors.initials: A
authors.lastname: Viale
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Victor
authors.initials: V
authors.lastname: Reuter
authors.affiliation: Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Bernard H
authors.initials: BH
authors.lastname: Bochner
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Rosenberg
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Dean F
authors.initials: DF
authors.lastname: Bajorin
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.affiliation: Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, New York. taylorb@mskcc.org petrinij@mskcc.org solitd@mskcc.org.
authors.forename: John H J
authors.initials: JH
authors.lastname: Petrini
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Department of Medicine, Weill Cornell Medical College, New York, New York. taylorb@mskcc.org petrinij@mskcc.org solitd@mskcc.org.
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.affiliation: Department of Medicine, University of California, San Francisco, California. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California. Department of Epidemiology and Biostatistics, University of California, San Francisco, California. taylorb@mskcc.org petrinij@mskcc.org solitd@mskcc.org.
authors.forename: Barry S
authors.initials: BS
authors.lastname: Taylor
mesh_terms: D017766:Acid Anhydride Hydrolases; D000595:Amino Acid Sequence; D064007:Ataxia Telangiectasia Mutated Proteins / Q000172:deficiency* / Q000235:genetics; D056915:DNA Copy Number Variations; D004249:DNA Damage; D045643:DNA Repair Enzymes / Q000737:chemistry / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D004789:Enzyme Activation; D023281:Genomics; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D010766:Phosphorylation; D011487:Protein Conformation; D016415:Sequence Alignment; D016896:Treatment Outcome
chemical_list: D004268:DNA-Binding Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes