Long-Term ERK Inhibition in KRAS-Mutant Pancreatic Cancer Is Associated with MYC Degradation and Senescence-like Growth Suppression

Tikvah K. Hayes, Nicole F. Neel, Chaoxin Hu, Prson Gautam, Melissa Chenard, Brian Long, Meraj Aziz, Michelle Kassner, Kirsten L. Bryant, Mariaelena Pierobon, Raoud Marayati, Swapnil Kher, Samuel D. George, Mai Xu, Andrea Wang-Gillam, Ahmed A. Samatar, Anirban Maitra, Krister Wennerberg, Emanuel F. Petricoin, Hongwei H. YinBarry Nelkin, Adrienne D. Cox, Jen Jen Yeh, Channing J. Der

Research output: Contribution to journalArticlepeer-review

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. Hayes et al. report an ERK inhibition-mediated growth suppression mechanism involving MYC degradation that is associated with the induction of a senescence-like phenotype in KRAS-mutant pancreatic cancer cells. Inhibitor combinations that enhance the effect of ERK inhibitor are also identified.

Original languageEnglish (US)
Pages (from-to)75-89
Number of pages15
JournalCancer cell
Volume29
Issue number1
DOIs
StatePublished - Jan 11 2016

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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