Journal
NATURE MEDICINE
Volume 24, Issue 7, Pages 961-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41591-018-0023-9
Keywords
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Funding
- Center for Cancer Genomics (CGC.NL)
- Dutch Cancer Society (KWF)
- EMBO Long-Term Fellowship [ALTF 1184-2014]
- European Commission (Marie Curie Actions, LTFCOFUND2013) [GA-2013-609409]
- Associazione Italiana per la Ricerca sul Cancro (AIRC)
- European Union
- European Community's Seventh Framework Programme [602901]
- Horizon 2020 grant [635342-2]
- IMI [115749 CANCER-ID]
- AIRC 2010 Special Program Molecular Clinical Oncology 5 per mille [9970]
- AIRC IG [16788]
- Fondazione Piemontese per la Ricerca sul Cancro-ONLUS 5 per mille Ministero della Salute
- Fondo de Investigaciones Sanitarias, FIS [PI16-01898, PI14-01109]
- Spanish Association Against Cancer, AECC [CGB14142035THOM]
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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.
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