## 1 Introduction  
Cancer tissues typically display a hierarchical organization reflected by the existence of rare yet highly malignant stem-like tumor-initiating cells (TIC) and more abundant differentiated progeny. TICs are key to cancer initiation and growth, display less sensitivity to chemotherapeutic, and are endowed with self-renewal and metastatic capacity. They are frequently enriched in advanced, aggressive, and/or resistant tumors, and cells isolated from distant metastases often show a TIC phenotype [1; 2]. A better understanding of the key molecular drivers and pathways accounting for the malignant properties of TICs is, therefore, of high therapeutic relevance. On a molecular level, the hedgehog (HH)--GLI signaling pathway has been crucially implicated in the regulation of self-renewal, disseminating, and tumor-initiating capacity of TICs [3; 4; 5; 6; 7]. This pivotal role of HH--GLI in TICs makes targeted pharmacological inhibition of HH--GLI signaling a promising therapeutic strategy to combat some of the major challenges in oncology such as patients' relapse and metastases formation. The HH signaling pathway is of central importance during embryonic development and regeneration, where it controls a multitude of biological processes such as cell proliferation, differentiation, survival, cell metabolism, and stem cell fate. In line with its various key roles, aberrant activity of the pathway in humans is causally linked with several developmental syndromes and malignancies [8; 9; 10; 11]. Canonical HH signaling starts with binding of the HH ligand protein to its receptor, Patched1 (PTCH1), a twelve-transmembrane domain protein which represses HH signaling in its unliganded state by inhibiting the transport of the G-protein-coupled receptor-like transmembrane protein, Smoothened (SMO), into the primary cilium [12]. In its activated state, SMO promotes the formation of active glioma-associated oncogene homolog (GLI) transcription factors by releasing GLI2/3 from their repressor, suppressor of fused (SUFU), thereby preventing proteolytic processing of GLI2/3. The unprocessed, full-length GLI proteins are then able to activate the expression of HH target genes, which promote tumor formation by inducing proliferation, anti-apoptotic signals, metastasis, cancer stem cell (CSC) self-renewal as well as expression of GLI1, leading to a strong positive feedback circuit. Furthermore, GLI1 expression serves as a reliable readout for HH--GLI pathway activation (for reviews, see [13; 14; 15; 16; 17]). The first inhibitors of oncogenic HH--GLI that were approved by the FDA for the treatment of advanced and metastatic basal cell carcinoma (BCC) were the small molecule SMO inhibitors (SMOi), vismodegib and sonidegib [18; 19; 20; 21; 22]. More recently, the third SMOi glassdegib has been approved for the treatment of acute myeloid leukemia in combination with low-dose cytarabine [23]. Although the SMO inhibitors demonstrate remarkable therapeutic efficacy, they are also associated with severe side effects, such as muscle cramps, weight and hair loss, and taste disturbance. These adverse effects very frequently force discontinuation of the treatment [24]. However, drug withdrawal is often followed by tumor relapse, due to the existence of resistant tumors cells. Here, it is noteworthy that SMO inhibitors alone rarely eliminate all tumor cells, which allows residual tumor cells to persist and regrow [24]. A substantial proportion of BCC patients showing SMOi resistance express mutant SMO variants. Such mutations in SMO occur either directly in the SMO inhibitor-binding pocket or outside of the binding pocket in pivotal regions of the transmembrane-helices, abolishing or attenuating the antagonistic activity of SMOi drugs. Additionally, resistance to SMO inhibitors can be caused by GLI2 amplification or genetic loss of the GLI repressor SUFU [25; 26; 27; 28; 29].