Abstract 462: Hyperactivation of ERK/MAPK pathway reduces pancreatic cancer cells' proliferation and tumor progression through phosphoproteome reprogramming

• Published in: Cancer research (Chicago, Ill.) Ill.), 2018-07, Vol.78 (13_Supplement), p.462-462
• Main Authors: Rowell, Marie-Camille, Deschênes-Simard, Xavier, Calvé, Benjamin Le, Lopes-Paciência, Stéphane, Ruiz, Ana Fernandez, Kottakis, Filippos, Bardeesy, Nabeel, Ferbeyre, Gerardo
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2018-462

This study aims to better understand the loss of tumor -uppression functions of ERK in pancreatic cancer progression. Pancreatic cancer is the 4th leading cause of death by cancer in Canada and USA with a 5-year survival rate below 7%. We have identified a high level of phosphorylation of the MAP kinase ERK in benign pancreatic intraepithelial neoplasms (PanIN), followed by a reduction in phospho-ERK levels in pancreatic ductal adenocarcinoma (PDAC) both in human patient samples and KRas-driven mouse models for pancreatic cancer. Since PanINs are considered senescent lesions, we hypothesized that phospho-ERK levels were reduced in PDAC to bypass oncogene-induced senescence and allow tumor initiation. We propose that reactivating high ERK in PDAC could restore tumor-suppression mechanisms lost during progression. To do so, we use a tamoxifen-inducible constitutive allele of RAF1 kinase, which acts upstream of ERK (ΔRAF1-ERT). In human (PANC-1, KP-4) and murine PDAC cell lines, activated RAF1 slows cell proliferation and induces cellular senescence in vitro in an ERK-dependent and p53/p16-independent manner. Activation of ERK kinases by this system in subcutaneous PDAC xenografts slows tumor growth in nude mice. To characterize key mediators of ERK-dependent tumor suppression, we did phosphoproteomics by mass spectrometry and identified a reprogramming of nuclear vs. cytoplasmic phosphoproteome, involving key ribosome biogenesis factors. Depletion of these nucleolar targets by shRNAs and nucleolar stress inducers such as RNA polymerase I inhibitor CX-5461 recapitulates ERK-dependent tumor suppression. At the same time, we are also investigating autophagy-related processes involved in RAF/MEK signaling blockade in PDAC cells. In summary, we suggest that high levels of p-ERK1/2 in early PanIN stage act as a tumor-suppressor mechanism, which is lost with cancer progression. Our future work aims to better understand the mechanism by which high ERK signaling exerts tumor suppression in order to find downstream effectors that could be used as therapeutic targets in pancreatic cancer. Citation Format: Marie-Camille Rowell, Xavier Deschênes-Simard, Benjamin Le Calvé, Stéphane Lopes-Paciência, Ana Fernandez Ruiz, Filippos Kottakis, Nabeel Bardeesy, Gerardo Ferbeyre. Hyperactivation of ERK/MAPK pathway reduces pancreatic cancer cells' proliferation and tumor progression through phosphoproteome reprogramming [abstract]. In: Proceedings of the American Association for C