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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Neel, B. G., Gu, H. & Pao, L. The ‘Shp’ing news: SH2 domain-containing tyrosine phosphatases in cell signaling. Trends Biochem. Sci. 28, 284–293 (2003).

  2. 2.

    Xu, D. & Qu, C.-K. Protein tyrosine phosphatases in the JAK/STAT pathway. Front. Biosci. 13, 4925–4932 (2008).

  3. 3.

    Chan, G., Kalaitzidis, D. & Neel, B. G. The tyrosine phosphatase Shp2 (PTPN11) in cancer. Cancer Metastasis Rev. 27, 179–192 (2008).

  4. 4.

    Matozaki, T., Murata, Y., Saito, Y., Okazawa, H. & Ohnishi, H. Protein tyrosine phosphatase SHP-2: a proto-oncogene product that promotes Ras activation. Cancer Sci. 100, 1786–1793 (2009).

  5. 5.

    Chan, R. J. & Feng, G.-S. PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase. Blood 109, 862–867 (2006).

  6. 6.

    Bard-Chapeau, E. A. et al. Ptpn11/Shp2 acts as a tumor suppressor in hepatocellular carcinogenesis. Cancer Cell 19, 629–639 (2011).

  7. 7.

    Grossmann, K. S., Rosário, M., Birchmeier, C. & Birchmeier, W. The tyrosine phosphatase Shp2 in development and cancer. Adv. Cancer Res. 106, 53–89 (2010).

  8. 8.

    Chen, Y.-N. P. et al. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases. Nature 535, 148–152 (2016).

  9. 9.

    Cox, A. D., Fesik, S. W., Kimmelman, A. C., Luo, J. & Der, C. J. Drugging the undruggable RAS: mission possible? Nat. Rev. Drug Discov. 13, 828–851 (2014).

  10. 10.

    Almoguera, C. et al. Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell 53, 549–554 (1988).

  11. 11.

    Zheng, J. et al. Pancreatic cancer risk variant in LINC00673 creates a miR-1231 binding site and interferes with PTPN11 degradation. Nat. Genet. 48, 747–757 (2016).

  12. 12.

    Schneeberger, V. E. et al. Inhibition of Shp2 suppresses mutant EGFR-induced lung tumors in transgenic mouse model of lung adenocarcinoma. Oncotarget 6, 6191–6202 (2015).

  13. 13.

    Xu, J., Zeng, L.-F., Shen, W., Turchi, J. J. & Zhang, Z.-Y. Targeting SHP2 for EGFR inhibitor resistant non-small cell lung carcinoma. Biochem. Biophys. Res. Commun. 439, 586–590 (2013).

  14. 14.

    Vogel, W., Lammers, R., Huang, J. & Ullrich, A. Activation of a phosphotyrosine phosphatase by tyrosine phosphorylation. Science 259, 1611–1614 (1993).

  15. 15.

    Feng, G. S., Hui, C. C. & Pawson, T. SH2-containing phosphotyrosine phosphatase as a target of protein-tyrosine kinases. Science 259, 1607–1611 (1993).

  16. 16.

    Lu, W., Shen, K. & Cole, P. A. Chemical dissection of the effects of tyrosine phosphorylation of SHP-2. Biochemistry 42, 5461–5468 (2003).

  17. 17.

    Hingorani, S. R. et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4, 437–450 (2003).

  18. 18.

    Jackson, E. L. et al. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev. 15, 3243–3248 (2001).

  19. 19.

    Means, A. L. et al. Pancreatic epithelial plasticity mediated by acinar cell transdifferentiation and generation of nestin-positive intermediates. Development 132, 3767–3776 (2005).

  20. 20.

    Aguirre, A. J. et al. Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev. 17, 3112–3126 (2003).

  21. 21.

    Bardeesy, N. et al. Both p16Ink4a and the p19Arf–p53 pathway constrain progression of pancreatic adenocarcinoma in the mouse. Proc. Natl Acad. Sci. USA 103, 5947–5952 (2006).

  22. 22.

    Collisson, E. A. et al. A central role for RAF→MEK→ERK signaling in the genesis of pancreatic ductal adenocarcinoma. Cancer Discov. 2, 685–693 (2012).

  23. 23.

    Blasco, R. B. et al. c-Raf, but not B-Raf, is essential for development of K-Ras oncogene-driven non-small cell lung carcinoma. Cancer Cell 19, 652–663 (2011).

  24. 24.

    di Magliano, M. P. & Logsdon, C. D. Roles for KRAS in pancreatic tumor development and progression. Gastroenterology 144, 1220–1229 (2013).

  25. 25.

    Srinivasan, L. et al. PI3 kinase signals BCR-dependent mature B cell survival. Cell 139, 573–586 (2009).

  26. 26.

    Eser, S. et al. Selective requirement of PI3K/PDK1 signaling for Kras oncogene-driven pancreatic cell plasticity and cancer. Cancer Cell 23, 406–420 (2013).

  27. 27.

    Lesina, M. et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 19, 456–469 (2011).

  28. 28.

    Schönhuber, N. et al. A next-generation dual-recombinase system for time- and host-specific targeting of pancreatic cancer. Nat. Med. 20, 1340–1347 (2014).

  29. 29.

    Prahallad, A. et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 483, 100–103 (2012).

  30. 30.

    Corcoran, R. B. et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2, 227–235 (2012).

  31. 31.

    Sun, C. et al. Intrinsic resistance to MEK inhibition in KRAS mutant lung and colon cancer through transcriptional induction of ERBB3. Cell Rep. 7, 86–93 (2014).

  32. 32.

    Pettazzoni, P. et al. Genetic events that limit the efficacy of MEK and RTK inhibitor therapies in a mouse model of KRAS-driven pancreatic cancer. Cancer Res. 75, 1091–1101 (2015).

  33. 33.

    Prahallad, A. et al. PTPN11 is a central node in intrinsic and acquired resistance to targeted cancer drugs. Cell Rep. 12, 1978–1985 (2015).

  34. 34.

    Manchado, E. et al. A combinatorial strategy for treating KRAS-mutant lung cancer. Nature 534, 647–651 (2016).

  35. 35.

    Infante, J. R. et al. A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas. Eur. J. Cancer 50, 2072–2081 (2014).

  36. 36.

    Jänne, P. A. et al. Selumetinib plus docetaxel compared with docetaxel alone and progression-free survival in patients with KRAS-mutant advanced non-small cell lung cancer: the SELECT-1 randomized clinical trial. JAMA 317, 1844–1853 (2017).

  37. 37.

    Grosskopf, S. et al. Selective inhibitors of the protein tyrosine phosphatase SHP2 block cellular motility and growth of cancer cells in vitro and in vivo. ChemMedChem 10, 815–826 (2015).

  38. 38.

    Garcia Fortanet, J. et al. Allosteric inhibition of SHP2: identification of a potent, selective, and orally efficacious phosphatase inhibitor. J. Med. Chem. 59, 7773–7782 (2016).

  39. 39.

    Alagesan, B. et al. Combined MEK and PI3K inhibition in a mouse model of pancreatic cancer. Clin. Cancer Res. 21, 396–404 (2015).

  40. 40.

    Caunt, C. J., Sale, M. J., Smith, P. D. & Cook, S. J. MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road. Nat. Rev. Cancer 15, 577–592 (2015).

  41. 41.

    Mainardi, S. et al. SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo. Nat. Med. https://doi.org/10.1038/s41591-018-0023-9 (2018).

  42. 42.

    Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545–15550 (2005).

  43. 43.

    Nakhai, H. et al. Ptf1a is essential for the differentiation of GABAergic and glycinergic amacrine cells and horizontal cells in the mouse retina. Development 134, 1151–1160 (2007).

  44. 44.

    Zhang, E. E., Chapeau, E., Hagihara, K. & Feng, G.-S. Neuronal Shp2 tyrosine phosphatase controls energy balance and metabolism. Proc. Natl Acad. Sci. USA 101, 16064–16069 (2004).

  45. 45.

    Marino, S., Vooijs, M., van Der Gulden, H., Jonkers, J. & Berns, A. Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. Genes Dev. 14, 994–1004 (2000).

  46. 46.

    Yasukawa, H. et al. IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Nat. Immunol. 4, 551–556 (2003).

  47. 47.

    Lee, C.-L. et al. Generation of primary tumors with Flp recombinase in FRT-flanked p53 mice. Dis. Model. Mech. 5, 397–402 (2012).

  48. 48.

    Mazur, P. K. et al. Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma. Nat. Med. 21, 1163–1171 (2015).

  49. 49.

    DuPage, M., Dooley, A. L. & Jacks, T. Conditional mouse lung cancer models using adenoviral or lentiviral delivery of Cre recombinase. Nat. Protoc. 4, 1064–1072 (2009).

  50. 50.

    Hellmuth, K. et al. Specific inhibitors of the protein tyrosine phosphatase Shp2 identified by high-throughput docking. Proc. Natl Acad. Sci. USA 105, 7275–7280 (2008).

  51. 51.

    Lan, L. et al. Shp2 signaling suppresses senescence in PyMT-induced mammary gland cancer in mice. EMBO J. 34, 1493–1508 (2015).

  52. 52.

    Chou, T.-C. Drug combination studies and their synergy quantification using the Chou–Talalay method. Cancer Res. 70, 440–446 (2010).

  53. 53.

    Boj, S. F. et al. Organoid models of human and mouse ductal pancreatic cancer. Cell 160, 324–338 (2015).

Download references


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.).

Author information


  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


  1. Search for Dietrich A. Ruess in:

  2. Search for Guus J. Heynen in:

  3. Search for Katrin J. Ciecielski in:

  4. Search for Jiaoyu Ai in:

  5. Search for Alexandra Berninger in:

  6. Search for Derya Kabacaoglu in:

  7. Search for Kivanc Görgülü in:

  8. Search for Zahra Dantes in:

  9. Search for Sonja M. Wörmann in:

  10. Search for Kalliope N. Diakopoulos in:

  11. Search for Angeliki F. Karpathaki in:

  12. Search for Marlena Kowalska in:

  13. Search for Ezgi Kaya-Aksoy in:

  14. Search for Liang Song in:

  15. Search for Eveline A. Zeeuw van der Laan in:

  16. Search for María P. López-Alberca in:

  17. Search for Marc Nazaré in:

  18. Search for Maximilian Reichert in:

  19. Search for Dieter Saur in:

  20. Search for Mert M. Erkan in:

  21. Search for Ulrich T. Hopt in:

  22. Search for Bruno Sainz Jr in:

  23. Search for Walter Birchmeier in:

  24. Search for Roland M. Schmid in:

  25. Search for Marina Lesina in:

  26. Search for Hana Algül in:


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.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Hana Algül.

Supplementary information

About this article

Publication history






Further reading