Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo

Nature Medicine volume 24, pages 961–967 (2018)Cite this article

Abstract

RAS mutations are frequent in human cancer, especially in pancreatic, colorectal and non-small-cell lung cancers (NSCLCs)1,2,3. Inhibition of the RAS oncoproteins has proven difficult4, and attempts to target downstream effectors5,6,7 have been hampered by the activation of compensatory resistance mechanisms8. It is also well established that KRAS-mutant tumors are insensitive to inhibition of upstream growth factor receptor signaling. Thus, epidermal growth factor receptor antibody therapy is only effective in KRAS wild-type colon cancers9,10. Consistently, inhibition of SHP2 (also known as PTPN11), which links receptor tyrosine kinase signaling to the RAS–RAF–MEK–ERK pathway11,12, was shown to be ineffective in KRAS-mutant or BRAF-mutant cancer cell lines13. Our data also indicate that SHP2 inhibition in KRAS-mutant NSCLC cells under normal cell culture conditions has little effect. By contrast, SHP2 inhibition under growth factor–limiting conditions in vitro results in a senescence response. In vivo, inhibition of SHP2 in KRAS-mutant NSCLC also provokes a senescence response, which is exacerbated by MEK inhibition. Our data identify SHP2 inhibition as an unexpected vulnerability of KRAS-mutant NSCLC cells that remains undetected in cell culture and can be exploited therapeutically.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: SHP2 inactivation sensitizes KRAS-mutant lung cancer cells to MEK inhibition.
Fig. 2: SHP2 inhibition affects KRASG12V GTP loading status.
Fig. 3: SHP2 inactivation induces senescence and impairs tumor growth in xenograft models of KRAS-mutant tumors.
Fig. 4: SHP2 inhibition induces senescence and impairs tumor growth in PDX models of KRAS-mutant NSCLC.

Similar content being viewed by others

References

  1. Cancer Genome Atlas Research Network. The Cancer Genome Atlas Pan-Cancer analysis project. Nat. Genet. 45, 1113–1120 (2013).

  2. Molina, J. R., Yang, P., Cassivi, S. D., Schild, S. E. & Adjei, A. A. Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship. Mayo Clin. Proc. 83, 584–594 (2008).

    Article  PubMed  Google Scholar 

  3. Forbes, S. A. et al. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res. 39, D945–D950 (2011).

    Article  PubMed  CAS  Google Scholar 

  4. Stephen, A. G., Esposito, D., Bagni, R. K. & McCormick, F. Dragging Ras back in the ring. Cancer Cell 25, 272–281 (2014).

    Article  PubMed  CAS  Google Scholar 

  5. Flaherty, K. T. et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N. Engl. J. Med. 367, 107–114 (2012).

    Article  PubMed  CAS  Google Scholar 

  6. Zhao, Y. & Adjei, A. A. The clinical development of MEK inhibitors. Nat. Rev. Clin. Oncol. 11, 385–400 (2014).

    Article  PubMed  CAS  Google Scholar 

  7. Wang, D., Boerner, S. A., Winkler, J. D. & LoRusso, P. M. Clinical experience of MEK inhibitors in cancer therapy. Biochim. Biophys. Acta. 1773, 1248–1255 (2007).

    Article  PubMed  CAS  Google Scholar 

  8. Bernards, R. A missing link in genotype-directed cancer therapy. Cell 151, 465–468 (2012).

    Article  PubMed  CAS  Google Scholar 

  9. Karapetis, C. S. et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N. Engl. J. Med. 359, 1757–1765 (2008).

    Article  PubMed  CAS  Google Scholar 

  10. De Roock, W. et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 11, 753–762 (2010).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  12. Chan, R. J. & Feng, G. S. PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase. Blood 109, 862–867 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  14. 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).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  18. Wu, T. R. et al. SHP-2 is a dual-specificity phosphatase involved in Stat1 dephosphorylation at both tyrosine and serine residues in nuclei. J. Biol. Chem. 277, 47572–47580 (2002).

    Article  PubMed  CAS  Google Scholar 

  19. Taylor, S. J., Resnick, R. J. & Shalloway, D. Nonradioactive determination of Ras-GTP levels using activated ras interaction assay. Methods Enzymol. 333, 333–342 (2001).

    Article  PubMed  CAS  Google Scholar 

  20. Waters, A. M. et al. Evaluation of the selectivity and sensitivity of isoform- and mutation-specific RAS antibodies. Sci. Signal 10, eaao3332 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Coppe, J. P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6, 2853–2868 (2008).

    Article  PubMed  CAS  Google Scholar 

  22. Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031 (2008).

    Article  PubMed  CAS  Google Scholar 

  23. Eggert, T. et al. Distinct functions of senescence-associated immune responses in liver tumor surveillance and tumor progression. Cancer Cell 30, 533–547 (2016).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  24. Hunter, J. C. et al. Biochemical and structural analysis of common cancer-associated KRAS mutations. Mol. Cancer Res. 13, 1325–1335 (2015).

    Article  PubMed  CAS  Google Scholar 

  25. Lu, S., Jang, H., Nussinov, R. & Zhang, J. The structural basis of oncogenic mutations G12, G13 and Q61 in small GTPase K-Ras4B. Sci. Rep. 6, 21949 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Fridman, A. L. & Tainsky, M. A. Critical pathways in cellular senescence and immortalization revealed by gene expression profiling. Oncogene 27, 5975–5987 (2008).

    Article  PubMed  CAS  Google Scholar 

  27. Purcell, M., Kruger, A. & Tainsky, M. A. Gene expression profiling of replicative and induced senescence. Cell Cycle 13, 3927–3937 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Hernandez-Segura, A. et al. Unmasking transcriptional heterogeneity in senescent cells. Curr. Biol. 27, 2652–2660 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Byrne, A. T. et al. Interrogating open issues in cancer precision medicine with patient-derived xenografts. Nat. Rev. Cancer 17, 254–268 (2017).

    Article  PubMed  CAS  Google Scholar 

  30. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Ruess, D. A. et al. Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase. Nat. Med. https://doi.org/10.1038/s41591-018-0024-8 (2018).

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. 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).

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  35. Herold, M. J., van den Brandt, J., Seibler, J. & Reichardt, H. M. Inducible and reversible gene silencing by stable integration of an shRNA-encoding lentivirus in transgenic rats. Proc. Natl. Acad. Sci. USA 105, 18507–18512 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Ambrogio, C. et al. Combined inhibition of DDR1 and Notch signaling is a therapeutic strategy for KRAS-driven lung adenocarcinoma. Nat. Med. 22, 270–277 (2016).

    Article  PubMed  CAS  Google Scholar 

  37. Jonkers, J. et al. Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat. Genet. 29, 418–425 (2001).

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank the Intervention Unit of the Mouse Clinic for Cancer and Aging (MCCA) of the Netherlands Cancer Institute, in particular, M. v. d. Ven and N. Proost, for the technical support with in vivo studies. We are grateful to pathologist H. Horlings for evaluation and scoring of in vivo samples. We are grateful to the NCI RAS Initiative for the kind gift of the panel of Rasless cells reconstituted with mutant KRAS alleles. This work was supported by grants from the Center for Cancer Genomics (CGC.NL) and the Dutch Cancer Society (KWF). S.M. was financially supported by an EMBO Long-Term Fellowship (ALTF 1184-2014) co-funded by the European Commission FP7 (Marie Curie Actions, LTFCOFUND2013, GA-2013-609409). G.G. was supported by an iCare fellowship by the Associazione Italiana per la Ricerca sul Cancro (AIRC) co-funded by the European Union. A. Bardelli was supported by the European Community’s Seventh Framework Programme under grant agreement no. 602901 MErCuRIC, Horizon 2020 grant agreement no. 635342-2 MoTriColor, IMI contract no. 115749 CANCER-ID, AIRC 2010 Special Program Molecular Clinical Oncology 5 per mille, Project no. 9970 Extension program, AIRC IG no. 16788, Fondazione Piemontese per la Ricerca sul Cancro-ONLUS 5 per mille 2011 e 2014 Ministero della Salute. A.V. and E.N. were supported by the Fondo de Investigaciones Sanitarias, FIS (PI16-01898 (to A.V.) and PI14-01109 (to E.N.)), and by the Spanish Association Against Cancer, AECC (CGB14142035THOM) (to A.V.).

Author information

Author notes

  1. Anirudh Prahallad

    Present address: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland

Authors and Affiliations

  1. Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Sara Mainardi, Antonio Mulero-Sánchez, Anirudh Prahallad, Astrid Bosma, Cor Lieftink & Rene Bernards

  2. Candiolo Cancer Institute—FPO, IRCCS, Turin, Italy

    Giovanni Germano & Alberto Bardelli

  3. Department of Oncology, University of Turin, Turin, Italy

    Giovanni Germano & Alberto Bardelli

  4. Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Paul Krimpenfort

  5. Mouse Clinic for Cancer and Aging (MCCA) Imaging Unit, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Jeffrey D. Steinberg & Niels de Wit

  6. Group of Chemoresistance and Predictive Factors, Subprogram Against Cancer Therapeutic Resistance (ProCURE), ICO, Oncobell Program, IDIBELL, L’Hospitalet del Llobregat, Barcelona, Spain

    Samuel Gonçalves-Ribeiro & Alberto Villanueva

  7. Thoracic Oncology Unit, Department of Medical Oncology, Catalan Institute of Oncology (ICO), L’Hospitalet del Llobregat, Barcelona, Spain

    Ernest Nadal

  8. Xenopat S.L., Business Bioincubator, Bellvitge Health Science Campus, Barcelona, Spain

    Alberto Villanueva

Authors
  1. Sara Mainardi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Antonio Mulero-Sánchez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anirudh Prahallad
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Giovanni Germano
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Astrid Bosma
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Paul Krimpenfort
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Cor Lieftink
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jeffrey D. Steinberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Niels de Wit
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Samuel Gonçalves-Ribeiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ernest Nadal
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Alberto Bardelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Alberto Villanueva
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Rene Bernards
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

R.B. supervised the work. R.B., S.M. and A.P. designed the experiments. S.M., A.M.-S., A.P. and A. Bosma performed the experiments and analyzed the data. C.L. analyzed the data. P.K. designed the genetically engineered mouse model experiments. J.D.S. and N.d.W. acquired and analyzed the MRI data. A. Bardelli designed and G.G. carried out the xenograft experiments. A.V., E.N. and S.G.-R. designed and carried out the PDX and PDOX experiments. R.B. and S.M. wrote the paper.

Corresponding author

Correspondence to Rene Bernards.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–11 and Supplementary Table 1

Reporting Summary

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mainardi, S., Mulero-Sánchez, A., Prahallad, A. et al. SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo. Nat Med 24, 961–967 (2018). https://doi.org/10.1038/s41591-018-0023-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41591-018-0023-9

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing