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Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase

Item Type:Article
Title:Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase
Creators Name:Ruess, D.A. and Heynen, G.J. and Ciecielski, K.J. and Ai, J. and Berninger, A. and Kabacaoglu, D. and Görgülü, K. and Dantes, Z. and Wörmann, S.M. and Diakopoulos, K.N. and Karpathaki, A.F. and Kowalska, M. and Kaya-Aksoy, E. and Song, L. and Zeeuw van der Laan, E.A. and López-Alberca, M.P. and Nazaré, M. and Reichert, M. and Saur, D. and Erkan, M.M. and Hopt, U.T. and Sainz, B. and Birchmeier, W. and Schmid, R.M. and Lesina, M. and Algül, H.
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. 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. 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. 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.
Source:Nature Medicine
ISSN:1078-8956
Publisher:Nature Publishing Group (U.S.A.)
Volume:24
Number:7
Page Range:954-960
Date:July 2018
Official Publication:https://doi.org/10.1038/s41591-018-0024-8
PubMed:View item in PubMed

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