GLI1 and cancer: Apart from mutational activation of canonical HH/GLI signaling, several cancer entities with high medical need display noncanonical, SMO-independent mechanisms involving a number of prominent oncogenic players, e.g., RAS/MEK/ERK, PI3K/AKT, JAK/STAT, epigenetic modifiers or various members of distinct kinase families (for details, see below) that directly or indirectly impinge on and enhance GLI activity.