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Identifying and exploiting defects in the Fanconi anemia/BRCA pathway in oncology

  • Shane R. Stecklein
    Affiliations
    Department of Pathology and Laboratory Medicine and The University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, Kan
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  • Roy A. Jensen
    Correspondence
    Reprint requests: Roy A. Jensen, MD, The University of Kansas Cancer Center, University of Kansas Medical Center, 3901 Rainbow Boulevard, Mail Stop 1027, Kansas City, KS 66160
    Affiliations
    Department of Pathology and Laboratory Medicine and The University of Kansas Cancer Center, University of Kansas Medical Center, Kansas City, Kan
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Published:February 10, 2012DOI:https://doi.org/10.1016/j.trsl.2012.01.022
      Defects in components of DNA repair pathways are responsible for numerous hereditary cancer syndromes and are also common in many sporadic malignancies. Inherited mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 or components of the Fanconi anemia (FA) complex incite genomic instability and predispose to malignancy. The products of the BRCA and FA genes participate in a conserved DNA damage repair pathway that is responsible for repairing interstrand crosslinks and double-strand DNA breaks by homologous recombination. While the genetic instability resulting from FA/BRCA dysfunction contributes to cancer pathogenesis, deficiency of these genes also lends to therapeutic exploitation. Crosslinking agents and ionizing radiation induce damage in cancer cells that requires the FA/BRCA pathway to be resolved; thus cancers that are deficient in BRCA1, BRCA2, or any other component of the FA/BRCA pathway are hypersensitive to these agents. Moreover, emerging synthetic lethal strategies offer opportunities to selectively target cancer cells with defects in homologous recombination. Conversely, enhanced activity of the FA/BRCA pathway is responsible for acquired resistance to specific therapeutic agents, suggesting that both dysfunction and hyperfunction of the FA/BRCA repair machinery are rational targets for cancer therapy. Selection of specific cytotoxic agents based on repair capacity may improve responses and enable personalized cytotoxic chemotherapy. This article reviews the FA/BRCA pathway and current approaches to identify deficiencies within it, discusses synthetic lethality and enhanced repair capacity as causes of therapeutic hypersensitivity and resistance, respectively, and highlights recent studies that have linked FA/BRCA pathway function with therapeutic efficacy.

      Abbreviations:

      17-AAG (17-allylamino-17-demethoxygeldanamycin), ATM (Ataxia telangiectasia mutatated (gene)), ATR (Ataxia telangiectasia and Rad3-related (gene)), AZD-2281 (Olaparib), BER (Base excision repair), BRCA1 (Breast cancer susceptibility gene 1 (gene)), BRCA2 (Breast cancer susceptibility gene 2 (gene) [same as FANCD1]), BRIP1 (BRCA1-associated C-terminal helicase (gene) [same as FANCJ]), BSI-201 (Iniparib), cCR (Clinical complete response), CDK1 (Cyclin-dependent kinase 1 (gene)), CDK5 (Cyclin-dependent kinase 5 (gene)), CHK1 (Checkpoint kinase 1 (gene)), CHK2 (Checkpoint kinase 2 (gene)), CpG (Cytosine-phosphate-guanine dinucleotide), 137Cs (Cesium-137), DAPI (4'-6-diamidino-2-phenylindole), DDN (2,3-dichloro-5,8-dihydroxy-1,4-naphthoquinone), DDR (DNA damage response), DEB (Diepoxybutane), DN (Dominant negative), DNA (Deoxyribonucleic acid), DSB (Double-strand break), EC (Epirubicin plus cyclophosphamide), EOC (Epithelial ovarian cancer), ER (Estrogen receptor), ESR1 (Estrogen receptor 1 (gene)), FA (Fanconi anemia), FAAP24 (Fanconi anemia-associated protein 24 (gene)), FAN1 (Fanconi anemia-associated nuclease 1 (gene)), FANCA (Fanconi anemia, complementation group A (gene)), FANCB (Fanconi anemia, complementation group B (gene)), FANCC (Fanconi anemia, complementation group C (gene)), FANCD1 (Fanconi anemia, complementation group D1 (gene) [same as BRCA2]), FANCD2 (Fanconi anemia, complementation group D2 (gene)), FANCE (Fanconi anemia, complementation group E (gene)), FANCF (Fanconi anemia, complementation group F (gene)), FANCG (Fanconi anemia, complementation group G (gene)), FANCI (Fanconi anemia, complementation group I (gene)), FANCJ (Fanconi anemia, complementation group J (gene) [same as BRIP1]), FANCL (Fanconi anemia, complementation group L (gene)), FANCM (Fanconi anemia, complementation group M (gene)), FANCN (Fanconi anemia, complementation group N (gene) [same as PALB2]), FANCO (Fanconi anemia, complementation group O (gene) [same as RAD51C]), FANCP (Fanconi anemia, complementation group P (gene)), GSTP1 (Glutathione S-transferase pi 1 (gene)), GSK3β (Glycogen synthase kinase 3 beta (gene)), Gy (Gray), γH2AX (H2A histone family, member X (pS139)), H2AX (H2A histone family, member X (gene)), HBOC (Hereditary breast and/or ovarian cancer), HER2 (Avian erythroblastic leukemia viral oncogene homolog 2 (gene)), HNPCC (Hereditary non-polyposis colorectal cancer), HR (Homologous recombination), HSP90 (Heat shock protein 90), ICL (Interstrand crosslink), ICLR (Interstrand crosslink repair), IR (Ionizing radiation), LOH (Loss of heterozygosity), MAI (Mitotic activity index), MGMT (O-6-methylguanine-DNA methyltransferase (gene)), MHF (FANCM-associated histone fold 1/2 (gene)), miRNA (MicroRNA), MLH1 (mutL homolog 1 (gene)), MMC (Mitomycin C), MMR (Mismatch repair), mRNA (Messenger RNA), MSH2 (mutS homolog 2 (gene)), NER (Nucleotide excision repair), NHEJ (Non-homologous end joining), PALB2 (Partner and localizer of BRCA2 (gene) [same as FANCN]), PARP (Poly(ADP)ribose polymerase), pCR (Pathologic complete response), PCR (Polymerase chain reaction), PI3K (Phosphatidylinositol-3 kinase), PKC (Protein kinase C), PR (Progesterone receptor), RAD51 (recA homolog (gene)), ssDNA (single-strand DNA), TN (Triple-negative), TP53 (p53) (Tumor protein 53 (gene))
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