Utilizing isogenic cells as well as several EC cell lines that have previously been established from Type I cancers to model disease biology,14, 15 including FGFR2‐mutant MFE280,16 MFE29616 and AN3CA,17 as well as FGFR2‐wild type (WT) SKUT1B,18 Ishikawa19 and KLE,20 we show that the most common EC‐linked mutations in FGFR2 (S252W and N550K21) significantly increase the sensitivity of FGF7 ligand–mediated ADAM17 activity, leading to increased shedding of HB‐EGF. Here, ADAM17 is linked to cancer.