In vivo Therapeutic Responses Contingent on Fanconi Anemia/BRCA2 Status of the Tumor

• Published in: Clinical cancer research Vol. 11; no. 20; pp. 7508 - 7515
• Main Authors: VAN DER HEIJDEN, Michiel S, BRODY, Jonathan R, KERN, Scott E, DEZENTJE, David A, GALLMEIER, Eike, CUNNINGHAM, Steven C, SWARTZ, Michael J, DEMARZO, Angelo M, OFFERHAUS, G. Johan A, ISACOFF, William H, HRUBAN, Ralph H
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-10-2005
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Biological and medical sciences; BRCA1, BRCA2; BRCA2 Protein - deficiency; BRCA2 Protein - genetics; Caspases - metabolism; Cell Cycle - drug effects; Cell Line, Tumor; Cell Survival - drug effects; Chemotherapy; Chlorambucil - pharmacology; Chromosome fragility (bloom syndrome, ataxia telangiectasia, fanconi anemia, x-linked mental retardation...); Cisplatin - pharmacology; Cross-Linking Reagents - pharmacology; Cross-Linking Reagents - therapeutic use; Deoxycytidine - analogs & derivatives; Deoxycytidine - pharmacology; DNA damage and repair mechanisms; Dose-Response Relationship, Drug; Doxorubicin - pharmacology; Etoposide - pharmacology; Fanconi Anemia Complementation Group C Protein - deficiency; Fanconi Anemia Complementation Group C Protein - genetics; Fanconi Anemia Complementation Group G Protein - deficiency; Fanconi Anemia Complementation Group G Protein - genetics; Fanconi Anemia Complementation Group Proteins - deficiency; Fanconi Anemia Complementation Group Proteins - genetics; Female; Fluorouracil - pharmacology; Gastrointestinal cancers: other; Humans; Inhibitory Concentration 50; Medical genetics; Medical sciences; Melphalan - pharmacology; Mice; Mice, Nude; Mitomycin - pharmacology; Mitomycin - therapeutic use; Mutation; Paclitaxel - pharmacology; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - pathology; Pharmacogenetics/pharmacogenomics; Pharmacology. Drug treatments; Time Factors; Vinblastine - pharmacology; Xenograft Model Antitumor Assays - methods; Xenograft models; Antineoplastic agent; Chromosome fragility; In vivo; Treatment; Fanconi anemia; BRCA2 gene; Crosslinking; Hemopathy; Genetic disease; Tumor suppressor gene
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-1048

Purpose: BRCA2, FANCC , and FANCG gene mutations are present in a subset of pancreatic cancer. Defects in these genes could lead to hypersensitivity to interstrand
cross-linkers in vivo and a more optimal treatment of pancreatic cancer patients based on the genetic profile of the tumor.
Experimental Design: Two retrovirally complemented pancreatic cancer cell lines having defects in the Fanconi anemia pathway, PL11 ( FANCC -mutated) and Hs766T ( FANCG -mutated), as well as several parental pancreatic cancer cell lines with or without mutations in the Fanconi anemia/BRCA2
pathway, were assayed for in vitro and in vivo sensitivities to various chemotherapeutic agents.
Results: A distinct dichotomy of drug responses was observed. Fanconi anemia–defective cancer cells were hypersensitive to the cross-linking
agents mitomycin C (MMC), cisplatin, chlorambucil, and melphalan but not to 5-fluorouracil, gemcitabine, doxorubicin, etoposide,
vinblastine, or paclitaxel. Hypersensitivity to cross-linking agents was confirmed in vivo ; FANCC -deficient xenografts of PL11 and BRCA2 -deficient xenografts of CAPAN1 regressed on treatment with two different regimens of MMC whereas Fanconi anemia–proficient
xenografts did not. The MMC response comprised cell cycle arrest, apoptosis, and necrosis. Xenografts of PL11 also regressed
after a single dose of cyclophosphamide whereas xenografts of genetically complemented PL11 FANCC did not.
Conclusions: MMC or other cross-linking agents as a clinical therapy for pancreatic cancer patients with tumors harboring defects in the
Fanconi anemia/BRCA2 pathway should be specifically investigated.