Recent studies indicate a role of ligand- and SMO-independent non-canonical HH signaling via phosphoinositide 3-kinase (PI3K)/AKT as shown in renal cell carcinoma and esophageal adenocarcinoma or TGFβ/SMAD in pancreatic cancer [9–11]. The gene discussed is AKT1; the disease is esophageal adenocarcinoma.