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

Sara Mainardi, Antonio Mulero-Sánchez, Anirudh Prahallad, Giovanni Germano, Astrid Bosma, Paul Krimpenfort, Cor Lieftink, Jeffrey D. Steinberg, Niels De Wit, Samuel Gonçalves-Ribeiro, Ernest Nadal, Alberto Bardelli, Alberto Villanueva, Rene Bernards

Research output: Contribution to journalArticle

Abstract

RAS mutations are frequent in human cancer, especially in pancreatic, colorectal and non-small-cell lung cancers (NSCLCs) 1-3 . Inhibition of the RAS oncoproteins has proven difficult 4, and attempts to target downstream effectors 5-7 have been hampered by the activation of compensatory resistance mechanisms 8 . 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 cancers 9,10 . Consistently, inhibition of SHP2 (also known as PTPN11), which links receptor tyrosine kinase signaling to the RAS-RAF-MEK-ERK pathway 11,12, was shown to be ineffective in KRAS-mutant or BRAF-mutant cancer cell lines 13 . 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.

Original languageEnglish
Pages (from-to)961-967
Number of pages7
JournalNature Medicine
Volume24
Issue number7
DOIs
Publication statusPublished - Jul 1 2018

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Mainardi, S., Mulero-Sánchez, A., Prahallad, A., Germano, G., Bosma, A., Krimpenfort, P., Lieftink, C., Steinberg, J. D., De Wit, N., Gonçalves-Ribeiro, S., Nadal, E., Bardelli, A., Villanueva, A., & Bernards, R. (2018). SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo letter. Nature Medicine, 24(7), 961-967. https://doi.org/10.1038/s41591-018-0023-9