title: Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy.
abstract: Pancreatic ductal adenocarcinoma (PDA) is a lethal disease. Overall survival is typically 6 months from diagnosis. Numerous phase 3 trials of agents effective in other malignancies have failed to benefit unselected PDA populations, although patients do occasionally respond. Studies in other solid tumors have shown that heterogeneity in response is determined, in part, by molecular differences between tumors. Furthermore, treatment outcomes are improved by targeting drugs to tumor subtypes in which they are selectively effective, with breast and lung cancers providing recent examples. Identification of PDA molecular subtypes has been frustrated by a paucity of tumor specimens available for study. We have overcome this problem by combined analysis of transcriptional profiles of primary PDA samples from several studies, along with human and mouse PDA cell lines. We define three PDA subtypes: classical, quasimesenchymal and exocrine-like, and we present evidence for clinical outcome and therapeutic response differences between them. We further define gene signatures for these subtypes that may have utility in stratifying patients for treatment and present preclinical model systems that may be used to identify new subtype specific therapies.
authors: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA.
authors: Eric A
authors: EA
authors: Collisson
authors: Anguraj
authors: A
authors: Sadanandam
authors: Peter
authors: P
authors: Olson
authors: William J
authors: WJ
authors: Gibb
authors: Morgan
authors: M
authors: Truitt
authors: Shenda
authors: S
authors: Gu
authors: Janine
authors: J
authors: Cooc
authors: Jennifer
authors: J
authors: Weinkle
authors: Grace E
authors: GE
authors: Kim
authors: Lakshmi
authors: L
authors: Jakkula
authors: Heidi S
authors: HS
authors: Feiler
authors: Andrew H
authors: AH
authors: Ko
authors: Adam B
authors: AB
authors: Olshen
authors: Kathleen L
authors: KL
authors: Danenberg
authors: Margaret A
authors: MA
authors: Tempero
authors: Paul T
authors: PT
authors: Spellman
authors: Douglas
authors: D
authors: Hanahan
authors: Joe W
authors: JW
authors: Gray
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000145:classification* / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D000069347:Erlotinib Hydrochloride; D005260:Female; D050993:GATA6 Transcription Factor / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D010190:Pancreatic Neoplasms / Q000145:classification* / Q000188:drug therapy / Q000235:genetics*; D010597:Pharmacogenetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000494:pharmacology; D018631:ras Proteins / Q000235:genetics; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D050993:GATA6 Transcription Factor; C494759:GATA6 protein, human; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D003841:Deoxycytidine; D000069347:Erlotinib Hydrochloride; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000093542:Gemcitabine