Format

Send to

Choose Destination
Nat Med. 2018 Jul;24(7):961-967. doi: 10.1038/s41591-018-0023-9. Epub 2018 May 28.

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

Author information

1
Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
2
Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
3
Candiolo Cancer Institute-FPO, IRCCS, Turin, Italy.
4
Department of Oncology, University of Turin, Turin, Italy.
5
Division of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
6
Mouse Clinic for Cancer and Aging (MCCA) Imaging Unit, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
7
Group of Chemoresistance and Predictive Factors, Subprogram Against Cancer Therapeutic Resistance (ProCURE), ICO, Oncobell Program, IDIBELL, L'Hospitalet del Llobregat, Barcelona, Spain.
8
Thoracic Oncology Unit, Department of Medical Oncology, Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, Barcelona, Spain.
9
Xenopat S.L., Business Bioincubator, Bellvitge Health Science Campus, Barcelona, Spain.
10
Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. r.bernards@nki.nl.

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 difficult4, and attempts to target downstream effectors5-7 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.

PMID:
29808006
DOI:
10.1038/s41591-018-0023-9

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center