Pancreatic cancer acquires resistance to MAPK pathway inhibition by clonal expansion and adaptive DNA hypermethylation.

"availability of data and materials proteomics data have been deposited as a complete submission in the proteomexchange consortium via the pride partner repository ( http://www proteomexchange org ; data set identifier: pxd018093 and 10 6019/pxd018093).; the rna-seq generated during this study is available at geo: gse146348.; the accession number for wgbs and wgs data deposited on ena is: prjeb37018."

"Declarations Ethics approval and consent to participateFor this study, already established patient-derived xenografts of pancreatic adenocarcinoma from three different male patients at passage number 2 were received from ARC-NET, University of Verona. The materials used have been collected under Program 1885 protocol 52438 on 23/11/2010 and Program 2172 protocol 26773CE 23/05/2012. The protocols include informed consent of the patients and were approved by the local ethics committee of the Integrated University Hospital Trust of Verona. All mice experiments were carried out by D. Behrens at EPO GmbH, Berlin-Buch, and performed according to the German Animal Protection Law with approval from the responsible authorities. The in vivo procedures were consistent and in compliance with the UKCCCR guidelines. Consent for publicationNot applicable. Competing interestsJ.T.S. receives honoraria as consultant or for continuing medical education presentations from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Immunocore, MSD Sharp Dohme, Novartis, Roche/Genentech, and Servier. His institution receives research funding from Abalos Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eisbach Bio, and Roche/Genentech; he holds ownership and serves on the Board of Directors of Pharma15, all outside the submitted work. Competing interests J.T.S. receives honoraria as consultant or for continuing medical education presentations from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Immunocore, MSD Sharp Dohme, Novartis, Roche/Genentech, and Servier. His institution receives research funding from Abalos Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eisbach Bio, and Roche/Genentech; he holds ownership and serves on the Board of Directors of Pharma15, all outside the submitted work."

"Funding Open Access funding enabled and organized by Projekt DEAL. This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) through 405344257 (SI1549/3–2) and 421166016 (SI1549/4–1), by the German Federal Ministry of Education and Research (BMBF; 01KD2206A/SATURN3), the European Unions Seventh Framework Programme for research, technological development and demonstration (FP7/CAM-PaC) under grant agreement no° 602783, and the research network CANcer TARgeting (CANTAR) of the Ministry of Culture and Science of the State of North Rhine-Westphalia (MKW NRW). J.T.S. receives funding from the German Cancer Consortium (DKTK). K.U.L is supported by the DFG (LU-1944/3-1) and is member of the DFG-funded Cluster of Excellence ImmunoSensation - EXC2151 – 390873048. A.S and R.T.L. are supported by Associazione Italiana Ricerca sul Cancro (AIRC 5 × 1000 n. 12182) and Fondazione Cariverona: Oncology Biobank Project “Antonio Schiavi” (prot. 203885/2017). This work was supported by PURE (Protein research Unit Ruhr within Europe) funded by the Ministry of Science, North Rhine-Westphalia, Germany. Disclaimer: This communication reflects the views of the authors, and the Joint Undertaking is not liable for any use that may be made of the information contained herein."