Herein, using 2D and 3D cultures of endometrial cancer cell lines expressing either wild-type or mutant FGFR2 as model systems, we have interrogated the mechanisms of acquired resistance to FGFR-targeted ATP mimetic small molecule therapies (Mohammadi et al., 1998, Gavine et al., 2012). The gene discussed is FGFR2; the disease is endometrial cancer.