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Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase

Nature Medicine volume 24, pages 954–960 (2018)Cite this article

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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 pathways1,2,3,4,5,6,7. 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.

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Fig. 1: Loss of Ptpn11 profoundly inhibits KRASG12D-driven pancreatic and pulmonary carcinogenesis.
Fig. 2: Oncogenic KRAS depends on SHP2 for adequate activity during carcinogenesis.
Fig. 3: Loss of SHP2 in established PDAC decelerates tumor progression and sensitizes to MEK inhibition.
Fig. 4: Dual MEK and SHP2 inhibition as a viable strategy to treat KRAS-mutant tumors.

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Acknowledgements

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 Ptpn11fl allele. We also thank R. F. Braren and D. C. Karampinos (both Institute of Radiology, Klinikum rechts der Isar, Technische Universität München) 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.; Max Eder Program no. 111273 to M.R.), the Wilhelm Sander Stiftung (2014.052.1 to H.A.) and the Fundación Asociación Española Contra el Cáncer (to B.S.).

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Authors and Affiliations

  1. Mildred-Scheel-Chair of Tumor Metabolism, Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

    Dietrich A. Ruess, 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, Maximilian Reichert, Dieter Saur, Roland M. Schmid, Marina Lesina & Hana Algül

  2. Department of Surgery, Faculty of Medicine, Medical Center—University of Freiburg, Freiburg, Germany

    Dietrich A. Ruess & Ulrich T. Hopt

  3. Cancer Research Program, Max Delbrück Center for Molecular Medicine (MDC) in the Helmholtz Society, Berlin, Germany

    Guus J. Heynen, Eveline A. Zeeuw van der Laan & Walter Birchmeier

  4. Medicinal Chemistry, Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany

    María P. López-Alberca & Marc Nazaré

  5. Koç University School of Medicine, Istanbul, Turkey

    Mert M. Erkan

  6. Department of Biochemistry, Autónoma University of Madrid, School of Medicine, Instituto de Investigaciones Biomédicas “Alberto Sols”, Madrid, Spain

    Bruno Sainz Jr

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Contributions

D.A.R., H.A. and G.J.H. conceived the study. D.A.R. conducted the animal experiments. D.A.R., A.B., D.K. and M.L. performed the histological scoring, immunohistochemistry and immunofluorescence. D.A.R., G.J.H., K.J.C., J.A., A.B. and E.A.Z.v.d.L. performed the immunoblotting. In vitro experiments with human PDAC cell lines including CRISPR–Cas9 knockout and reconstitution experiments were conducted by G.J.H. and E.A.Z.v.d.L. In vitro drug screening was done by K.J.C. and D.A.R. The oncogenomic database analysis and GSEAs were performed by D.A.R. Maintenance of mouse colonies and genotyping were performed by D.A.R., K.J.C., J.A., D.K., K.G., K.N.D., S.M.W., M.L., A.F.K., A.B., M.K., E.K.-A. and L.S. M.P.L.-A., M.N. and W.B. synthesized GS493 and SHP099. K.J.C., Z.D., D.A.R. and M.R. performed the ex vivo organoid assay. D.S. generated mutant mouse alleles. M.E. and B.S. established the PDAC-PDX. D.A.R., G.J.H., K.J.C. and H.A. analyzed the data. D.A.R., G.J.H. and K.J.C. generated the figures. D.A.R. and H.A. wrote the original draft, with input from B.S. and G.J.H. Supervision was provided by H.A. Funding was provided by H.A., M.L., M.R., U.T.H., R.M.S., B.S. and W.B. All authors critically revised and approved the manuscript.

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Correspondence to Hana Algül.

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Ruess, D.A., Heynen, G.J., Ciecielski, K.J. et al. Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase. Nat Med 24, 954–960 (2018). https://doi.org/10.1038/s41591-018-0024-8

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