alpha-Endorphin br Mechanisms of Resistance As with other ca

Mechanisms of Resistance As with other cancer treatments in development, resistance is a concern with HHIs. Most observations regarding HHI resistance originate from patients with BCC [78]. In the clinic, resistance to vismodegib and sonidegib were observed when used to treat advanced BCC [78], [79]. Acquired mutations in SMO cause resistance [78], [80], and neither vismodegib nor sonidegib are active against SMO D473H, a mutation reported in a number of HHI-resistant patients [79], [81]. Although some clinical results suggest that resistance to 1 HHI implies resistance to another HHI in the same class [79], data are conflicting [37]. Importantly, in a preclinical model of medulloblastoma, patidegib was effective on tumors resistant to vismodegib [82], suggesting a lack of cross-resistance in all instances. Additionally, binding of HHIs to mutant forms of Smo revealed that a mutation at residue 518 increased affinity for sonidegib, while concomitantly decreasing affinity for vismodegib [83], [84]. Amplification of downstream HH genes (eg, Gli2) as a mechanism of resistance has been reported for vismodegib and sonidegib in cultured alpha-Endorphin and a mouse model of medulloblastoma. The amplification correlated with tumor growth in a Smo-independent manner [4], [85], [86]. Mutations in genes controlling ciliogenesis are another mechanism of HHI resistance. For example, mutations in the ciliogenesis oral-facial-digital-syndrome-1 gene (Ofd1) lead to HHI resistance via the loss of primary cilia that regulate HH signaling [87]. The investigators noted that mutations in Ofd1 or in the HH signaling component gene Sufu conferred resistance to chemotherapy agents [87].
Potentials and Pitfalls of Hedgehog Inhibitors HH signaling is complex and plays a role not only in tumorigenesis but also drug resistance. Individual response to HHIs varies and detailed biomarker analyses should help to identify which patients are more suited to HHI therapy, which has significant AEs associated with reduced quality of life, drug tolerance, and patient adherence often leading to discontinuation [80]. Vismodegib and sonidegib have comparable efficacy and tolerability in the treatment of BCC; and if side effects arise, it may be possible to switch from one to the other, although most of the side effects are class-related [30], [74], [92], [93], [94]. Based on differences in CNS penetration, sonidegib might be selected in preference to other treatment options based on the presence of CNS disease (ie, medulloblastoma or metastasis) [95]. ATO and itraconazole are less efficient but could be used following resistance to SMO inhibitors [96]. However, for patidegib and glasdegib, it is currently unclear. Phase 3 trials are ongoing for topical patidegib (NCT03703310), which might prove to be a good option for BCCNS, but certainly not for visceral tumors [97]. The role of other inhibitors in hematological malignancies and glasdegib in other diseases beyond AML should be explored. Furthermore, additional combinational therapies might prove valuable, such as azacytidine and venetoclax, which is the new standard treatment for newly diagnosed AML patients aged 75 or older with comorbidities that preclude the use of intensive induction chemotherapy [98]. Overall, the benefit of HHI therapy often outweighs the negative side effects, and increased patient education and management may help to extend treatment and improve clinical outcomes [80].
Summary and Future Directions
Introduction Lung cancer is the leading cause of cancer related mortality globally and is classified as either Small Cell Lung Cancer (SCLC) or Non-Small Cell Lung Cancer (NSCLC) upon pathology review. [1,2] The main histologic types of NSCLC include squamous cell carcinoma and adenocarcinoma. [2] The majority of patients have non-curable disease stage at the time of diagnosis. Advances in systemic treatments including chemotherapy, targeted therapies and immune check point inhibitors have improved prognosis in recent years. Nevertheless, most patients with metastatic lung cancer die within a few years from diagnosis, stressing the need for more and novel therapeutic approaches. Targeted therapies benefit patients classified in well-defined molecular groups identified by the presence of activating mutations in key genes like EGFR, ALK, ROS1 and BRAF that follow the oncogene addiction paradigm. [3] The list of driver oncogenes with actionable mutations is expanding over time. On the other hand, targeting molecular pathways in the absence of an addicting oncogene mutation is a more challenging goal.