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

Authors' Affiliations: Departments of ¹ Oncology, ² Pathology, and ³ Radiation Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland; Departments of ⁴ Internal Medicine and ⁵ Pathology, Academic Medical Center, Amsterdam, the Netherlands; and ⁶ Department of Medicine, David-Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California

Requests for reprints: Scott E. Kern, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Room 451, Cancer Research Building, 1650 Orleans Street, Baltimore, MD 21231. Phone: 410-614-3314; Fax: 410-287-4653; E-mail: sk{at}jhmi.edu.

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.

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