Abstract
Induction of compensatory mechanisms and ERK reactivation has limited the effectiveness of Raf and MEK inhibitors in RAS-mutant cancers. We determined that direct pharmacologic inhibition of ERK suppressed the growth of a subset of KRAS-mutant pancreatic cancer cell lines and that concurrent phosphatidylinositol 3-kinase (PI3K) inhibition caused synergistic cell death. Additional combinations that enhanced ERK inhibitor action were also identified. Unexpectedly, long-term treatment of sensitive cell lines caused senescence, mediated in part by MYC degradation and p16 reactivation. Enhanced basal PI3K-AKT-mTOR signaling was associated with de novo resistance to ERK inhibitor, as were other protein kinases identified by kinome-wide siRNA screening and a genetic gain-of-function screen. Our findings reveal distinct consequences of inhibiting this kinase cascade at the level of ERK.
Copyright © 2016 Elsevier Inc. All rights reserved.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Cell Line, Tumor
-
Extracellular Signal-Regulated MAP Kinases / genetics
-
Extracellular Signal-Regulated MAP Kinases / metabolism*
-
MAP Kinase Signaling System / genetics*
-
Mice
-
Mitogen-Activated Protein Kinase Kinases / genetics
-
Mitogen-Activated Protein Kinase Kinases / metabolism
-
Pancreatic Neoplasms / genetics*
-
Pancreatic Neoplasms / metabolism
-
Phosphatidylinositol 3-Kinases / metabolism
-
Protein Kinase Inhibitors / pharmacology
-
Proto-Oncogene Proteins c-akt / metabolism
-
Proto-Oncogene Proteins c-myc / genetics*
-
Proto-Oncogene Proteins c-myc / metabolism
-
Proto-Oncogene Proteins p21(ras) / genetics*
-
Zeit
Substances
-
Myc protein, mouse
-
Protein Kinase Inhibitors
-
Proto-Oncogene Proteins c-myc
-
Proto-Oncogene Proteins c-akt
-
Extracellular Signal-Regulated MAP Kinases
-
Mitogen-Activated Protein Kinase Kinases
-
Hras protein, mouse
-
Proto-Oncogene Proteins p21(ras)