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

July 1, 2018

Indicated cells were cultured and seeded into 96-well plates at a density of 500–2,000 cells per well, depending on growth rate. Twenty-four hours later, drugs were added at the indicated concentrations using the HP D300 Digital Dispenser (HP). Cells were imaged every 4 h in IncuCyte ZOOM (Essen Bioscience). Phase-contrast images were analyzed to detect cell proliferation based on cell confluence

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.

Mainardi, S; Mulero-Sånchez, A; Prahallad, A; Germano, G; Bosma, A; Krimpenfort, P; Lieftink, C; Steinberg, JD; de Wit, N; Gonçalves-Ribeiro, S; Nadal, E; Bardelli, A; Villanueva, A; Bernards, R;

Journal: Nat. Med. Pages: 961-967

Original article (29808006)