Adaptive and Reversible Resistance to Kras Inhibition in Pancreatic Cancer Cells.

Cancer Res
Authors
Keywords
Abstract

Activating mutations in 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 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. These results call into question the degree to which pancreatic cancers are addicted to KRAS by illustrating adaptive nongenetic and nontranscriptional mechanisms of resistance to Kras blockade, with implications for the development of KRAS inhibitors for PDAC treatment. .

Year of Publication
2018
Journal
Cancer Res
Volume
78
Issue
4
Pages
985-1002
Date Published
2018 02 15
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-17-2129
PubMed ID
29279356
PubMed Central ID
PMC5837062
Links
Grant list
Howard Hughes Medical Institute / United States
K08 CA208016 / CA / NCI NIH HHS / United States
KL2 TR001100 / TR / NCATS NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States