title: Combined MEK and PI3K inhibition in a mouse model of pancreatic cancer.
abstract: OBJECTIVE
  Improved therapeutic approaches are needed for the treatment of pancreatic ductal adenocarcinoma (PDAC). As dual MEK and PI3K inhibition is presently being used in clinical trials for patients with PDAC, we sought to test the efficacy of combined targeting of these pathways in PDAC using both in vitro drug screens and genetically engineered mouse models (GEMM).
  
  
  METHODS
  We performed high-throughput screening of >500 human cancer cell lines (including 46 PDAC lines), for sensitivity to 50 clinically relevant compounds, including MEK and PI3K inhibitors. We tested the top hit in the screen, the MEK1/2 inhibitor, AZD6244, for efficacy alone or in combination with the PI3K inhibitors, BKM120 or GDC-0941, in a Kras(G12D)-driven GEMM that recapitulates the histopathogenesis of human PDAC.
  
  
  RESULTS
  In vitro screens revealed that PDAC cell lines are relatively resistant to single-agent therapies. The response profile to the MEK1/2 inhibitor, AZD6244, was an outlier, showing the highest selective efficacy in PDAC. Although MEK inhibition alone was mainly cytostatic, apoptosis was induced when combined with PI3K inhibitors (BKM120 or GDC-0941). When tested in a PDAC GEMM and compared with the single agents or vehicle controls, the combination delayed tumor formation in the setting of prevention and extended survival when used to treat advanced tumors, although no durable responses were observed.
  
  
  CONCLUSIONS
  Our studies point to important contributions of MEK and PI3K signaling to PDAC pathogenesis and suggest that dual targeting of these pathways may provide benefit in some patients with PDAC. Clin Cancer Res; 21(2); 396-404. ©2014 AACR.
authors.affiliation: Cancer Center, Massachusetts General Hospital, Boston, MA 02114.
authors.forename: Brinda
authors.initials: B
authors.lastname: Alagesan
authors.affiliation: Cancer Center, Massachusetts General Hospital, Boston, MA 02114.
authors.forename: Gianmarco
authors.initials: G
authors.lastname: Contino
authors.affiliation: Center for Molecular Imaging Research, Massachusetts General Hospital, Boston, MA 02114.|Department of Radiology, Harvard Medical School, Boston, MA 02115.
authors.forename: Alex R
authors.initials: AR
authors.lastname: Guimaraes
authors.affiliation: Cancer Center, Massachusetts General Hospital, Boston, MA 02114.|Department of Medicine, Harvard Medical School, Boston, MA 02115.
authors.forename: Ryan B
authors.initials: RB
authors.lastname: Corcoran
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, MA 02114.|Department of Pathology, Harvard Medical School, Boston, MA 02115.
authors.forename: Vikram
authors.initials: V
authors.lastname: Deshpande
authors.affiliation: Center for Molecular Imaging Research, Massachusetts General Hospital, Boston, MA 02114.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Wojtkiewicz
authors.affiliation: Cancer Center, Massachusetts General Hospital, Boston, MA 02114.|Department of Medicine, Harvard Medical School, Boston, MA 02115.
authors.forename: Aram F
authors.initials: AF
authors.lastname: Hezel
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston MA 02215.|Department of Medicine, Harvard Medical School, Boston, MA 02115.
authors.forename: Kwok-Kin
authors.initials: KK
authors.lastname: Wong
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston MA 02215.|Department of Radiology, Harvard Medical School, Boston, MA 02115.|Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: Massimo
authors.initials: M
authors.lastname: Loda
authors.affiliation: Center for Molecular Imaging Research, Massachusetts General Hospital, Boston, MA 02114.|Department of Radiology, Harvard Medical School, Boston, MA 02115.
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.affiliation: Cancer Center, Massachusetts General Hospital, Boston, MA 02114.|Department of Medicine, Harvard Medical School, Boston, MA 02115.
authors.forename: Cyril H
authors.initials: CH
authors.lastname: Benes
authors.affiliation: Cancer Center, Massachusetts General Hospital, Boston, MA 02114.|Department of Medicine, Harvard Medical School, Boston, MA 02115.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Engelman
authors.affiliation: Cancer Center, Massachusetts General Hospital, Boston, MA 02114.|Department of Medicine, Harvard Medical School, Boston, MA 02115.
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
mesh_terms: D000631:Aminopyridines; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D000069347:Erlotinib Hydrochloride; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D008822:Mice, Transgenic; D009025:Morpholines; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology
chemical_list: C517975:AZD 6244; D000631:Aminopyridines; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D009025:Morpholines; C571178:NVP-BKM120; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D020930:MAP Kinase Kinase Kinases