Upregulation of PI3K signaling has been linked to acquired resistance to SMO inhibitors for the re-expression of GLI1 in medulloblastoma (Buonamici et al., 2010), and proposed as a potential resistance mechanism for other tumors such as esophageal cancer (Wang et al., 2012), implying that a combinatorial approach targeting both canonical (with SMO inhibitors) and non-canonical GLI activation (via PI3K inhibitors) could delay tumor resistance (Buonamici et al., 2010; Dijkgraaf et al., 2011). The gene discussed is GLI1; the disease is esophageal cancer.