Journal Article

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

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

2018

Overview

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. Combined inhibition of SHP2 and MEK is an effective therapeutic approach in non-small-cell lung cancer.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Analysis / Antibodies / Biomedical and Life Sciences / Biomedicine / Cancer / Cancer Research / Cell culture / Colon / Epidermal growth factor / Epidermal growth factors / Extracellular signal-regulated kinase / Genetic aspects / Growth / Growth factors / Immunotherapy / Infectious Diseases / Inhibition / K-Ras protein / Letter / Lung cancer / Metabolic Diseases / Metabolic pathways / Molecular Medicine / Mutants / Mutation / Neurosciences / 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