title: K-RAS mutant pancreatic tumors show higher sensitivity to MEK than to PI3K inhibition in vivo.
abstract: Activating K-RAS mutations occur at a frequency of 90% in pancreatic cancer, and to date no therapies exist targeting this oncogene. K-RAS signals via downstream effector pathways such as the MAPK and the PI3K signaling pathways, and much effort has been focused on developing drugs targeting components of these pathways. To better understand the requirements for K-RAS and its downstream signaling pathways MAPK and PI3K in pancreatic tumor maintenance, we established an inducible K-RAS knock down system that allowed us to ablate K-RAS in established tumors. Knock down of K-RAS resulted in impaired tumor growth in all pancreatic xenograft models tested, demonstrating that K-RAS expression is indeed required for tumor maintenance of K-RAS mutant pancreatic tumors. We further examined signaling downstream of K-RAS, and detected a robust reduction of pERK levels upon K-RAS knock down. In contrast, no effect on pAKT levels could be observed due to almost undetectable basal expression levels. To investigate the requirement of the MAPK and the PI3K pathways on tumor maintenance, three selected pancreatic xenograft models were tested for their response to MEK or PI3K inhibition. Tumors of all three models regressed upon MEK inhibition, but showed less pronounced response to PI3K inhibition. The effect of MEK inhibition on pancreatic xenografts could be enhanced further by combined application of a PI3K inhibitor. These data provide further rationale for testing combinations of MEK and PI3K inhibitors in clinical trials comprising a patient population with pancreatic cancer harboring mutations in K-RAS.
authors.affiliation: Novartis Institutes for Biomedical Research, Oncology Disease Area, Basel, Switzerland. irmgard.hofmann@novartis.com
authors.forename: Irmgard
authors.initials: I
authors.lastname: Hofmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Weiss
authors.forename: Gaelle
authors.initials: G
authors.lastname: Elain
authors.forename: Maria
authors.initials: M
authors.lastname: Schwaederle
authors.forename: Dario
authors.initials: D
authors.lastname: Sterker
authors.forename: Vincent
authors.initials: V
authors.lastname: Romanet
authors.forename: Tobias
authors.initials: T
authors.lastname: Schmelzle
authors.forename: Albert
authors.initials: A
authors.lastname: Lai
authors.forename: Saskia M
authors.initials: SM
authors.lastname: Brachmann
authors.forename: Mohamed
authors.initials: M
authors.lastname: Bentires-Alj
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Roberts
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
authors.forename: Francesco
authors.initials: F
authors.lastname: Hofmann
authors.forename: Sauveur-Michel
authors.initials: SM
authors.lastname: Maira
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D013449:Sulfonamides / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics*
chemical_list: D001562:Benzimidazoles; D048049:Extracellular Signal-Regulated MAP Kinases; D007191:Indazoles; D020929:Mitogen-Activated Protein Kinase Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016283:Proto-Oncogene Proteins p21(ras); D013449:Sulfonamides; D018631:ras Proteins; C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; C517975:AZD 6244; C117307:KRAS protein, human