Long-Term ERK Inhibition in KRAS-Mutant Pancreatic Cancer Is Associated with MYC Degradation and Senescence-like Growth Suppression
Research output: Contribution to journal › Journal article › Research › peer-review
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.
Original language | English |
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Journal | Cancer Cell |
Volume | 29 |
Issue number | 1 |
Pages (from-to) | 75-89 |
Number of pages | 15 |
ISSN | 1535-6108 |
DOIs | |
Publication status | Published - 11 Jan 2016 |
Externally published | Yes |
- Animals, Cell Line, Tumor, Extracellular Signal-Regulated MAP Kinases/genetics, MAP Kinase Signaling System/genetics, Mice, Mitogen-Activated Protein Kinase Kinases/genetics, Pancreatic Neoplasms/genetics, Phosphatidylinositol 3-Kinases/metabolism, Protein Kinase Inhibitors/pharmacology, Proto-Oncogene Proteins c-akt/metabolism, Proto-Oncogene Proteins c-myc/genetics, Proto-Oncogene Proteins p21(ras)/genetics, Time
Research areas
ID: 199424845