Modeling targeted inhibition of MEK and PI3 kinase in human pancreatic cancer.
Activating mutations in the KRAS oncogene occur in approximately 90% of pancreatic cancers, resulting in aberrant activation of the MAPK and the PI3K pathways, driving malignant progression. Significant efforts to develop targeted inhibitors of nodes within these pathways are underway and several are currently in clinical trials for patients with KRAS-mutant tumors, including patients with pancreatic cancer. To model MEK and PI3K inhibition in late-stage pancreatic cancer, we conducted preclinical trials with a mutant Kras-driven genetically engineered mouse model that faithfully recapitulates human pancreatic ductal adenocarcinoma development. Treatment of advanced disease with either a MEK (GDC-0973) or PI3K inhibitor (GDC-0941) alone showed modest tumor growth inhibition and did not significantly enhance overall survival. However, combination of the two agents resulted in a significant survival advantage as compared with control tumor-bearing mice. To model the clinical scenario, we also evaluated the combination of these targeted agents with gemcitabine, the current standard-of-care chemotherapy for pancreatic cancer. The addition of MEK or PI3K inhibition to gemcitabine, or the triple combination regimen, incrementally enhanced overall survival as compared with gemcitabine alone. These results are reminiscent of the survival advantage conferred in this model and in patients by the combination of gemcitabine and erlotinib, an approved therapeutic regimen for advanced nonresectable pancreatic cancer. Taken together, these data indicate that inhibition of MEK and PI3K alone or in combination with chemotherapy do not confer a dramatic improvement as compared with currently available therapies for patients with pancreatic cancer.
Genentech Inc., South San Francisco, California. junttila.melissa@gene.com msingh@patronustx.com.
Melissa R
MR
Junttila
Genentech Inc., South San Francisco, California.
Vidusha
V
Devasthali
Genentech Inc., South San Francisco, California.
Jason H
JH
Cheng
Genentech Inc., South San Francisco, California.
Joseph
J
Castillo
Genentech Inc., South San Francisco, California.
Ciara
C
Metcalfe
Genentech Inc., South San Francisco, California.
Anne C
AC
Clermont
Genentech Inc., South San Francisco, California.
Douglas Den
DD
Otter
Genentech Inc., South San Francisco, California.
Emily
E
Chan
Genentech Inc., South San Francisco, California.
Hani
H
Bou-Reslan
Genentech Inc., South San Francisco, California.
Tim
T
Cao
Genentech Inc., South San Francisco, California.
William
W
Forrest
Genentech Inc., South San Francisco, California.
Michelle A
MA
Nannini
Genentech Inc., South San Francisco, California.
Dorothy
D
French
Genentech Inc., South San Francisco, California.
Richard
R
Carano
Genentech Inc., South San Francisco, California.
Mark
M
Merchant
Genentech Inc., South San Francisco, California.
Klaus P
KP
Hoeflich
Genentech Inc., South San Francisco, California. junttila.melissa@gene.com msingh@patronustx.com.
Mallika
M
Singh
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000494:pharmacology; D001384:Azetidines / Q000008:administration & dosage / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D059039:Standard of Care; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; D001384:Azetidines; D007191:Indazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D003841:Deoxycytidine; D048369:MAP Kinase Kinase 1; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); C574276:cobimetinib; D000093542:Gemcitabine