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.

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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

    • Anirudh Prahallad

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


  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


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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.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Rene Bernards.

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