SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo. (July 2018)

• Record Type: Journal Article
• Authors: Mainardi, Sara; Mulero-Sánchez, Antonio; Prahallad, Anirudh; Germano, Giovanni; Bosma, Astrid; Krimpenfort, Paul; Lieftink, Cor; Steinberg, Jeffrey; de Wit, Niels; Gonçalves-Ribeiro, Samuel; Nadal, Ernest; Bardelli, Alberto; Villanueva, Alberto; Bernards, Rene
• Is Part Of: Nature medicine. Volume 24:Number 7(2018)
• Page Start: 961
• Page End: 967
• Publication Date: 2018-07
• Subjects: Pathology, Molecular -- Periodicals; Molecular biology -- Periodicals; 610.724
• DOI: 10.1038/s41591-018-0023-9
• Languages: English
• ISSNs: 1078-8956

Abstract

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 thatKRAS -mutant tumors are insensitive to inhibition of upstream growth factor receptor signaling. Thus, epidermal growth factor receptor antibody therapy is only effective inKRAS 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 inKRAS -mutant orBRAF -mutant cancer cell lines13 . Our data also indicate that SHP2 inhibition inKRAS -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 inKRAS -mutant NSCLC also provokes a senescence response, which is exacerbated by MEK inhibition. Our data identify SHP2 inhibition as an unexpected vulnerability ofKRAS -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.