title: Targeting SRC in mucinous ovarian carcinoma.
abstract: OBJECTIVE
  Mucinous ovarian carcinomas have a distinct clinical pattern compared with other subtypes of ovarian carcinoma. Here, we evaluated (i) stage-specific clinical significance of mucinous ovarian carcinomas in a large cohort and (ii) the functional role of Src kinase in preclinical models of mucinous ovarian carcinoma.
  
  
  METHODS
  A total of 1,302 ovarian cancer patients including 122 (9.4%) cases of mucinous carcinoma were evaluated for survival analyses. Biological effects of Src kinase inhibition were tested using dasatinib-based therapy in a novel orthotopic mucinous ovarian cancer model (RMUG-S-ip2).
  
  
  RESULTS
  Patients with advanced-stage mucinous ovarian cancer had significantly worse survival than those with serous histology: median overall survival, 1.67 versus 3.41 years, P = 0.002; median survival time after recurrence of 0.53 versus 1.66 years, P < 0.0001. Among multiple ovarian cancer cell lines, RMUG-S-ip2 mucinous ovarian cancer cells showed the highest Src kinase activity. Moreover, oxaliplatin treatment induced phosphorylation of Src kinase. This induced activity by oxaliplatin therapy was inhibited by concurrent administration of dasatinib. Targeting Src with dasatinib in vivo showed significant antitumor effects in the RMUG-S-ip2 model but not in the serous ovarian carcinoma (SKOV3-TR) model. Combination therapy of oxaliplatin with dasatinib further showed significant effects on reducing cell viability, increasing apoptosis, and in vivo antitumor effects in the RMUG-S-ip2 model.
  
  
  CONCLUSIONS
  Our results suggest that poor survival of women with mucinous ovarian carcinoma is associated with resistance to cytotoxic therapy. Targeting Src kinase with a combination of dasatinib and oxaliplatin may be an attractive approach for this disease.
authors: Department of Gynecologic Oncology and Reproductive Medicine, MD Anderson Cancer Center, University of Texas, 77230, USA.
authors: Koji
authors: K
authors: Matsuo
authors: Masato
authors: M
authors: Nishimura
authors: Justin N
authors: JN
authors: Bottsford-Miller
authors: Jie
authors: J
authors: Huang
authors: Kakajan
authors: K
authors: Komurov
authors: Guillermo N
authors: GN
authors: Armaiz-Pena
authors: Mian M K
authors: MM
authors: Shahzad
authors: Rebecca L
authors: RL
authors: Stone
authors: Ju Won
authors: JW
authors: Roh
authors: Angela M
authors: AM
authors: Sanguino
authors: Chunhua
authors: C
authors: Lu
authors: Dwight D
authors: DD
authors: Im
authors: Neil B
authors: NB
authors: Rosenshien
authors: Atsuko
authors: A
authors: Sakakibara
authors: Tadayoshi
authors: T
authors: Nagano
authors: Masato
authors: M
authors: Yamasaki
authors: Takayuki
authors: T
authors: Enomoto
authors: Tadashi
authors: T
authors: Kimura
authors: Prahlad T
authors: PT
authors: Ram
authors: Kathleen M
authors: KM
authors: Schmeler
authors: Gary E
authors: GE
authors: Gallick
authors: Kwong K
authors: KK
authors: Wong
authors: Michael
authors: M
authors: Frumovitz
authors: Anil K
authors: AK
authors: Sood
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival; D000069439:Dasatinib; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077150:Oxaliplatin; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000077150:Oxaliplatin; D019061:src-Family Kinases; D000069439:Dasatinib