In vivo therapeutic responses contingent on fanconi anemia/BRCA2 status of the tumor

Michiel S. Van Der Heijden, Jonathan R. Brody, David A. Dezentje, Eike Gallmeier, Steven C. Cunningham, Michael J. Swartz, Angelo M. DeMarzo, G. Johan A. Offerhaus, William H. Isacoff, Ralph H. Hruban, Scott E. Kern

Research output: Contribution to journalArticlepeer-review

132 Scopus citations

Abstract

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 PL11FANCC did not. Conclusios: 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.

Original languageEnglish (US)
Pages (from-to)7508-7515
Number of pages8
JournalClinical Cancer Research
Volume11
Issue number20
DOIs
StatePublished - Oct 15 2005
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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