In vivo therapeutic responses contingent on Fanconi anemia/BRCA2 status of the tumor.
OBJECTIVE
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.


METHODS
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.
van der Heijden
Michiel S
MS
Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Brody
Jonathan R
JR
Dezentje
David A
DA
Gallmeier
Eike
E
Cunningham
Steven C
SC
Swartz
Michael J
MJ
DeMarzo
Angelo M
AM
Offerhaus
G Johan A
GJ
Isacoff
William H
WH
Hruban
Ralph H
RH
Kern
Scott E
SE
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D024682:BRCA2 Protein / Q000172:deficiency / Q000235:genetics; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002699:Chlorambucil / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000494:pharmacology* / Q000627:therapeutic use; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D052218:Fanconi Anemia Complementation Group C Protein / Q000172:deficiency / Q000235:genetics; D052241:Fanconi Anemia Complementation Group G Protein / Q000172:deficiency / Q000235:genetics; D051856:Fanconi Anemia Complementation Group Proteins / Q000172:deficiency / Q000235:genetics*; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008558:Melphalan / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D016685:Mitomycin / Q000494:pharmacology* / Q000627:therapeutic use; D009154:Mutation; D017239:Paclitaxel / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D013997:Time Factors; D014747:Vinblastine / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D024682:BRCA2 Protein; D003432:Cross-Linking Reagents; C497651:FANCC protein, human; C499909:FANCG protein, human; D052218:Fanconi Anemia Complementation Group C Protein; D052241:Fanconi Anemia Complementation Group G Protein; D051856:Fanconi Anemia Complementation Group Proteins; D003841:Deoxycytidine; D002699:Chlorambucil; D016685:Mitomycin; D014747:Vinblastine; D005047:Etoposide; D004317:Doxorubicin; D020169:Caspases; D017239:Paclitaxel; D002945:Cisplatin; D008558:Melphalan; D005472:Fluorouracil; D000093542:Gemcitabine