Abstract CN05-02: Targeting the Fanconi anemia/BRCA pathway.

Abstract

Abstract Cancer cells have genomic instability resulting from acquired defects in DNA repair. One DNA repair pathway, the Fanconi Anemia/BRCA homologous recombination pathway (Kennedy and D'Andrea, Genes & Development 19:2925, 2005), is defective in many human cancers, including breast, ovarian, pancreatic, and lung neoplasms. Disruption of the FA/BRCA Pathway results in the characteristic chromosome instability and radiation/crosslinker hypersensitivity of these tumors. In general, loss of one DNA repair pathway often leads to hyperdependence on another pathway for tumor cell survival. This hyperdependence offers a unique opportunity for the development of anticancer therapeutics. For instance, FA/BRCA pathway deficient tumors are hyperdependent on base excision repair (BER) and, accordingly, these tumors are hypersensitive to single agent treatment with PARP1 inhibitors which block BER. Our laboratory efforts are focused on profiling the FA/BRCA pathway and the other five major DNA repair pathways in tumor cells (Kennedy and D'Andrea, JCO 24: 3799, 2006). Each DNA repair pathway has a characteristic protein biomarker and repairs a specific type of DNA lesion. By profiling these pathways in primary tumor samples with activation-specific antibodies to DNA repair proteins, we are developing methods to: 1) predict the sensitivity of tumors to conventional chemotherapy and radiation (Personalized Medicine); 2) to subset tumors for their sensitivity to novel classes of DNA repair inhibitors (i.e., PARP1, Chk1, and ATM inhibitors); and 3) to screen for new small molecule inhibitors of other DNA repair pathways. This combination of novel DNA repair inhibitors, conventional DNA damaging agents, and DNA repair biomarkers offers new opportunities for developing more effective anticancer therapy. The FA/BRCA pathway was elucidated through the systematic study of the rare inherited chromosome breakage disorder, Fanconi Anemia (Moldovan and D'Andrea, Ann Rev Genet 43:223, 2009). FA is an autosomal recessive disease characterized by bone marrow failure, congenital malformations, and cellular sensitivity to cisplatin, mitomycin C, and other DNA interstrand crosslinking agents. Patients with FA develop hematopoietic malignancies and squamous cell carcinomas. Based on somatic cell fusion studies, there are sixteen FA complementation groups (A, B, C, D1, D2, E, F, G, I, J, L, M, N, O, P, Q), and the corresponding gene for each of these complementation groups has been identified. Interestingly, the sixteen FA proteins cooperate in a common cellular pathway in normal human cells, referred to as the Fanconi Anemia/BRCA pathway. Eight of the FA proteins (A, B, C, E, F, G, L, M) are assembled in a core complex (the FA core complex) which is an active ubiquitin E3 ligase. In response to DNA damage, the FA core complex modifies (monoubiquitinates) the downstream FANCD2 protein. Monoubiquitinated FANCD2 translocates to nuclear foci where it interacts with the FANCD1/BRCA2 protein and participates in the process of homologous recombination DNA repair. Additional FA proteins (namely, FANCJ/BRIP1 and FANCN/PALB2) function downstream of FANCD2 monoubiquitination. At least three of the FA genes (FANCD1, FANCJ, and FANCN) are inherited breast cancer susceptibility genes. Disruption of any step in the FA/BRCA pathway results in the common clinical and cellular phenotype of FA patients. Human tumor cells, derived from cancer patients from the general (non-FA) population, often exhibit genomic instability. Genomic instability of tumors has important clinical consequences. On the one hand, genomic instability gives the tumor the ability to break and fuse chromosomes, inactivate tumor suppressor genes, form novel oncogene fusions, and amplify drug resistance genes. Thus, the tumor with genomic instability may become more malignant and drug resistant over time. On the other hand, in order to achieve a state of genomic instability, a tumor cell must inactivate one of its major DNA repair pathways. This inactivation appears to account, at least in part, for the selective hypersensitivity of cancer cells to the cytotoxic effects of conventional anticancer radiation and chemotherapy. Recent studies indicate that some human tumors inactivate the FA/BRCA pathway. Pathway inactivation may result from somatic mutation of genes in the FA/BRCA pathway or by epigenetic silencing. For instance, methylation of one of the FA genes, FANCF, has been implicated as a mechanism for genomic instability in a wide variety of cancers, including ovarian, breast, lung, cervical, and head and neck squamous cell carcinomas. Somatic inactivation of the FA/BRCA pathway appears to account for the genomic instability and the cisplatin hypersensitivity of many of these cancers. In my presentation, I will review the features of the FA/BRCA pathway in human cells, and how knowledge of this pathway in cancers can lead to the prediction of drug response. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):CN05-02. Citation Format: Alan D. D'Andrea. Targeting the Fanconi anemia/BRCA pathway. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr CN05-02.