RT Journal Article
SR Electronic
T1 Epigenetic plasticity via adaptive DNA hypermethylation and clonal expansion underlie resistance to oncogenic pathway inhibition in pancreatic cancer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.05.20.492826
DO 10.1101/2022.05.20.492826
A1 Laura K. Godfrey
A1 Jan Forster
A1 Sven-Thorsten Liffers
A1 Christopher Schröder
A1 Johannes Köster
A1 Leonie Henschel
A1 Kerstin U. Ludwig
A1 Marija Trajkovic-Arsic
A1 Diana Behrens
A1 Aldo Scarpa
A1 Rita T. Lawlor
A1 Kathrin E. Witzke
A1 Barbara Sitek
A1 Steven A. Johnsen
A1 Sven Rahmann
A1 Bernhard Horsthemke
A1 Michael Zeschnigk
A1 Jens T. Siveke
YR 2022
UL http://biorxiv.org/content/early/2022/05/20/2022.05.20.492826.abstract
AB Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor prognosis. Drug resistance is the major cause for therapeutic failure in PDAC patients with progressive disease. The mechanisms underlying resistance formation are complex and remain poorly understood.To gain insights into molecular changes during the formation of resistance to oncogenic MAPK pathway inhibition we utilized short-term passaged primary tumor cells from ten PDACs of genetically engineered mice. We followed gain and loss of resistance upon MEKi exposure and withdrawal by longitudinal integrative analysis of whole genome sequencing, whole genome bisulfite sequencing, RNA-sequencing and mass spectrometry data.We found that resistant cell populations under increasing MEKi treatment evolved by the expansion of a single clone but were not a direct consequence of known resistance-conferring mutations. Rather, resistant cells showed adaptive DNA hypermethylation of 209 and hypomethylation of 8 genomic sites, most of which overlap with regulatory elements known to be active in murine PDAC cells. Both DNA methylation changes and MEKi resistance were transient and reversible upon drug withdrawal. The effector caspase CASP3 is one of the 114 genes for which transcriptional downregulation inversely correlated with the methylation status of the associated DNA region. CASP3 inactivation in resistant cells led to attenuation of drug-induced apoptosis which could be reversed by DNA methyltransferase inhibition with remarkable sensitivity exclusively in the resistant cells.Overall, our data provide a context for characterization and targeting of epigenetically mediated resistance mechanisms in PDAC.Competing Interest StatementJens Siveke reports institutional research funding from BMS, Celgene and Roche; compensated consulting from AstraZeneca, Bayer, Immunocore, Roche, Servier. He holds ownership and serves on the Board of Directors of Pharma15, all outside the submitted work. No disclosures were reported by the other authors.