Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2018-07

AUTHORS

Dietrich A. Ruess, Guus J. Heynen, Katrin J. Ciecielski, Jiaoyu Ai, Alexandra Berninger, Derya Kabacaoglu, Kivanc Görgülü, Zahra Dantes, Sonja M. Wörmann, Kalliope N. Diakopoulos, Angeliki F. Karpathaki, Marlena Kowalska, Ezgi Kaya-Aksoy, Liang Song, Eveline A. Zeeuw van der Laan, María P. López-Alberca, Marc Nazaré, Maximilian Reichert, Dieter Saur, Mert M. Erkan, Ulrich T. Hopt, Bruno Sainz, Walter Birchmeier, Roland M. Schmid, Marina Lesina, Hana Algül

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 receptors1. 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 pathways1-7. 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 vitro8. 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. More... »

PAGES

954-960

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41591-018-0024-8

DOI

http://dx.doi.org/10.1038/s41591-018-0024-8

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1104216241

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/29808009


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