Nature medicine, 2018-07, Vol.24 (7), p.961-967
2018
Details
- Autor(en) / Beteiligte
- Titel
- SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo
- Ist Teil von
- Nature medicine, 2018-07, Vol.24 (7), p.961-967
- Ort / Verlag
- United States: Nature Publishing Group
- Erscheinungsjahr
- 2018
- Link zum Volltext
- Beschreibungen/Notizen
- RAS mutations are frequent in human cancer, especially in pancreatic, colorectal and non-small-cell lung cancers (NSCLCs) . Inhibition of the RAS oncoproteins has proven difficult , and attempts to target downstream effectors have been hampered by the activation of compensatory resistance mechanisms . 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 . Consistently, inhibition of SHP2 (also known as PTPN11), which links receptor tyrosine kinase signaling to the RAS-RAF-MEK-ERK pathway , was shown to be ineffective in KRAS-mutant or BRAF-mutant cancer cell lines . 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1078-8956eISSN: 1546-170XDOI: 10.1038/s41591-018-0023-9Titel-ID: cdi_proquest_miscellaneous_2046607475
- Format
- –
- Schlagworte
- Analysis, Antibodies, Cancer, Cell culture, Colon, Epidermal growth factor, Epidermal growth factors, Extracellular signal-regulated kinase, Genetic aspects, Growth, Growth factors, Immunotherapy, Inhibition, K-Ras protein, Lung cancer, Lung cancer, Non-small cell, Metabolic pathways, Mutation, Non-small cell lung cancer, Non-small cell lung carcinoma, Pancreas, Pancreatic cancer, Phenols (Class of compounds), Protein-tyrosine kinase receptors, Raf protein, Ras genes, Senescence, Signaling, Tumors, Tyrosine