Adaptive and Reversible Resistance to Kras Inhibition in Pancreatic Cancer Cells
Abstract
Activating mutations in KRAS are the hallmark genetic alterations in pancreatic ductal adenocarcinoma (PDAC) and the key drivers of its initiation and progression. Longstanding efforts to develop novel KRAS inhibitors have been based on the assumption that PDAC cells are addicted to activated KRAS, but this assumption remains controversial. In this study, we analyzed the requirement of endogenous Kras to maintain survival of murine PDAC cells, using an inducible shRNA-based system that enables temporal control of Kras expression. We found that the majority of murine PDAC cells analyzed tolerated acute and sustained Kras silencing by adapting to a reversible cell state characterized by differences in cell morphology, proliferative kinetics, and tumor-initiating capacity. While we observed no significant mutational or transcriptional changes in the Kras-inhibited state, global phosphoproteomic profiling revealed significant alterations in cell signaling, including increased phosphorylation of focal adhesion pathway components. Accordingly, Kras-inhibited cells displayed prominent focal adhesion plaque structures, enhanced adherence properties, and increased dependency on adhesion for viability in vitro. Overall, our results call into question the degree to which PDAC cells are addicted to activated KRAS, by illustrating adaptive nongenetic and nontranscriptional mechanisms of resistance to Kras blockade. However, by identifying these mechanisms, our work also provides mechanistic directions to develop combination strategies that can help enforce the efficacy of KRAS inhibitors.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 14, 2018
- Source ID
- 10.1158/0008-5472.can-17-2129
Entities
People
- Amanda Del Rosario
- Anette Claudia Schafer
- Arjun Bhutkar
- Frank Gertler
- Jana Qiao
- Kimberly Judith Dorans
- Mandar Deepak Muzumdar
- Pan-yu Chen
- Philipp Mertins
- Rebecca Robbins
- Steven A Carr
- Tyler Jacks
Organizations
- Howard Hughes Medical Institute
- Lustgarten Foundation for Pancreatic Cancer Research
- Massachusetts Institute of Technology
- National Cancer Institute
- Pancreatic Cancer Action Network
- United States Department of Defense
- University of California, San Francisco
- Yale University