Publication: Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase
dc.contributor.coauthor | Ruess, Dietrich A. | |
dc.contributor.coauthor | Heynen, Guus J. | |
dc.contributor.coauthor | Ciecielski, Katrin J. | |
dc.contributor.coauthor | Ai, Jiaoyu | |
dc.contributor.coauthor | Berninger, Alexandra | |
dc.contributor.coauthor | Kabacaoglu, Derya | |
dc.contributor.coauthor | Goerguelue, Kivanc | |
dc.contributor.coauthor | Dantes, Zahra | |
dc.contributor.coauthor | Woermann, Sonja M. | |
dc.contributor.coauthor | Diakopoulos, Kalliope N. | |
dc.contributor.coauthor | Karpathaki, Angeliki F. | |
dc.contributor.coauthor | Kowalska, Marlena | |
dc.contributor.coauthor | Kaya-Aksoy, Ezgi | |
dc.contributor.coauthor | Song, Liang | |
dc.contributor.coauthor | van der Laan, Eveline A. Zeeuw | |
dc.contributor.coauthor | Lopez-Alberca, Maria P. | |
dc.contributor.coauthor | Nazare, Marc | |
dc.contributor.coauthor | Reichert, Maximilian | |
dc.contributor.coauthor | Saur, Dieter | |
dc.contributor.coauthor | Hopt, Ulrich T. | |
dc.contributor.coauthor | Sainz, Bruno, Jr. | |
dc.contributor.coauthor | Birchmeier, Walter | |
dc.contributor.coauthor | Schmid, Roland M. | |
dc.contributor.coauthor | Lesina, Marina | |
dc.contributor.coauthor | Alguel, Hana | |
dc.contributor.department | N/A | |
dc.contributor.kuauthor | Erkan, Murat Mert | |
dc.contributor.kuprofile | Faculty Member | |
dc.contributor.schoolcollegeinstitute | School of Medicine | |
dc.contributor.yokid | 214689 | |
dc.date.accessioned | 2024-11-10T00:08:40Z | |
dc.date.issued | 2018 | |
dc.description.abstract | The ubiquitously expressed non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, is involved in signal transduction downstream of multiple growth factor, cytokine and integrin receptors(1). Its requirement for complete RAS-MAPK activation and its role as a negative regulator of JAK-STAT signaling have established SHP2 as an essential player in oncogenic signaling pathways(1-7). Recently, a novel potent allosteric SHP2 inhibitor was presented as a viable therapeutic option for receptor tyrosine kinase-driven cancers, but was shown to be ineffective in KRAS-mutant tumor cell lines in vitro(8). Here, we report a central and indispensable role for SHP2 in oncogenic KRAS-driven tumors. Genetic deletion of Ptpn11 profoundly inhibited tumor development in mutant KRAS-driven murine models of pancreatic ductal adenocarcinoma and non-small-cell lung cancer. We provide evidence for a critical dependence of mutant KRAS on SHP2 during carcinogenesis. Deletion or inhibition of SHP2 in established tumors delayed tumor progression but was not sufficient to achieve tumor regression. However, SHP2 was necessary for resistance mechanisms upon blockade of MEK. Synergy was observed when both SHP2 and MEK were targeted, resulting in sustained tumor growth control in murine and human patient-derived organoids and xenograft models of pancreatic ductal adenocarcinoma and non-small-cell lung cancer. Our data indicate the clinical utility of dual SHP2/MEK inhibition as a targeted therapy approach for KRAS-mutant cancers. | |
dc.description.indexedby | WoS | |
dc.description.indexedby | Scopus | |
dc.description.indexedby | PubMed | |
dc.description.issue | 7 | |
dc.description.openaccess | YES | |
dc.description.publisherscope | International | |
dc.description.sponsoredbyTubitakEu | N/A | |
dc.description.sponsorship | Deutsche Forschungsgemeinschaft [DFG AL1174/5-1, LE3222/1-1] | |
dc.description.sponsorship | Deutsche Krebshilfe [111646, 111464, 111273] | |
dc.description.sponsorship | Wilhelm Sander Stiftung [2014.052.1] | |
dc.description.sponsorship | Fundacion Asociacion Espanola Contra el Cancer We thank G.-S. Feng (Department of Pathology, School of Medicine, and Molecular Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA, USA) for sharing the Ptpn11<SUP>fl</SUP> allele. We also thank R. F. Braren and D. C. Karampinos (both Institute of Radiology, Klinikum rechts der Isar, Technische Universitat Munchen) for providing the infrastructure and A. Gupta for help with the setup for MRI studies. This work was supported by grants from Deutsche Forschungsgemeinschaft (DFG AL1174/5-1 to H.A. and LE3222/1-1 to M.L.), Deutsche Krebshilfe (no. 111646 and no. 111464 to H.A. | |
dc.description.sponsorship | Max Eder Program no. 111273 to M.R.), the Wilhelm Sander Stiftung (2014.052.1 to H.A.) and the Fundacion Asociacion Espanola Contra el Cancer (to B.S.). | |
dc.description.volume | 24 | |
dc.identifier.doi | 10.1038/s41591-018-0024-8 | |
dc.identifier.eissn | 1546-170X | |
dc.identifier.issn | 1078-8956 | |
dc.identifier.quartile | Q1 | |
dc.identifier.scopus | 2-s2.0-85047784549 | |
dc.identifier.uri | http://dx.doi.org/10.1038/s41591-018-0024-8 | |
dc.identifier.uri | https://hdl.handle.net/20.500.14288/16969 | |
dc.identifier.wos | 438187700023 | |
dc.keywords | Mouse model | |
dc.keywords | Phosphotyrosine phosphatase | |
dc.keywords | Tyrosine phosphatases | |
dc.language | English | |
dc.publisher | Nature Publishing Group (NPG) | |
dc.source | Nature Medicine | |
dc.subject | Biochemistry | |
dc.subject | Molecular biology | |
dc.subject | Cell biology | |
dc.subject | Medicine | |
dc.subject | Research and experimental | |
dc.title | Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase | |
dc.type | Journal Article | |
dspace.entity.type | Publication | |
local.contributor.authorid | 0000-0002-2753-0234 | |
local.contributor.kuauthor | Erkan, Murat Mert |