title: Subtype-specific MEK-PI3 kinase feedback as a therapeutic target in pancreatic adenocarcinoma.
abstract: Mutations in the KRAS oncogene are dominant features in pancreatic ductal adenocarcinoma (PDA). Because KRAS itself is considered "undruggable," targeting pathways downstream of KRAS are being explored as a rational therapeutic strategy. We investigated the consequences of MAP-ERK kinase (MEK) inhibition in a large PDA cell line panel. Inhibition of MEK activated phosphoinositide 3-kinase in an EGF receptor (EGFR)-dependent fashion and combinations of MEK and EGFR inhibitors synergistically induced apoptosis. This combinatorial effect was observed in the epithelial but not mesenchymal subtype of PDA. RNA expression analysis revealed predictors of susceptibility to the combination, including E-cadherin, HER3, and the miR200-family of microRNAs, whereas expression of the transcription factor ZEB1 was associated with resistance to the drug combination. Knockdown of HER3 in epithelial-type and ZEB1 in mesenchymal-type PDA cell lines resulted in sensitization to the combination of MEK and EGFR inhibitors. Thus, our findings suggest a new, subtype-specific, and personalized therapeutic strategy for pancreatic cancer.
authors.affiliation: Corresponding Author: W. Michael Korn, UCSF Divisions of Gastroenterology and Hematology/Oncology, Helen Diller Family Comprehensive Cancer Center, 2340 Sutter St., Box 1387, San Francisco, CA 94115. Michael.Korn@ucsf.edu.
authors.forename: Olga K
authors.initials: OK
authors.lastname: Mirzoeva
authors.forename: Eric A
authors.initials: EA
authors.lastname: Collisson
authors.forename: Peter M
authors.initials: PM
authors.lastname: Schaefer
authors.forename: Byron
authors.initials: B
authors.lastname: Hann
authors.forename: Yun K
authors.initials: YK
authors.lastname: Hom
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Ko
authors.forename: W Michael
authors.initials: WM
authors.lastname: Korn
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D017209:Apoptosis; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000378:metabolism; D025461:Feedback, Physiological; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics*; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D058990:Molecular Targeted Therapy; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D000071799:Zinc Finger E-box-Binding Homeobox 1; D018631:ras Proteins / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; C117307:KRAS protein, human; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D020930:MAP Kinase Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
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