Chahal Kirti K, Parle Milind, Abagyan Ruben
Department of Pharmaceutical Sciences, G.J. University of Science and Technology, Hisar, India.
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California, USA.
Anticancer Drugs. 2018 Jun;29(5):387-401. doi: 10.1097/CAD.0000000000000609.
The hedgehog (Hh) pathway plays an important role in cancer development and maintenance, as ~25% of all cancers have aberrant Hh pathway activation. Targeted therapy for inhibition of the Hh pathway was thought to be promising for achieving clinical response in the Hh-dependent cancers. However, the results of new clinical trials with smoothened (SMO) antagonists do not show much success in cancers other than basal cell carcinoma. The studies suggest that the Hh pathway involves multiple mechanisms of activation or inhibition in primary cilia and interactions between several related pathways in different types of cells, which makes this pathway extremely complex. The SMO-specific antagonists may not stop all relevant pathways that may lead to escape or development of resistance. Therefore, in the Hh-dependent cancers, the inhibition of two or more oncogenic pathways (including the Hh pathway) with use of a single agent of a suitable multitarget profile or a combination of drugs seems promising for achieving clinical response in patients and decrease in resistance development with prolonged use of the specific SMO antagonists. Furthermore, for studying the effect of new treatments, the inclusion criteria should be more specific for selection of patients with aberrant Hh pathway activity confirmed by tests. These considerations will be very helpful for choosing the right patients and the right drugs for the best therapeutic outcome.
刺猬信号通路（Hh）在癌症发生和维持过程中发挥着重要作用，因为所有癌症中约25%存在Hh信号通路异常激活。抑制Hh信号通路的靶向治疗被认为有望在依赖Hh的癌症中取得临床疗效。然而，使用 smoothened（SMO）拮抗剂进行的新临床试验结果显示，除基底细胞癌外，在其他癌症中并未取得显著成功。研究表明，Hh信号通路涉及初级纤毛中多种激活或抑制机制，以及不同类型细胞中几种相关信号通路之间的相互作用，这使得该信号通路极其复杂。SMO特异性拮抗剂可能无法阻断所有可能导致耐药性产生或发展的相关信号通路。因此，在依赖Hh的癌症中，使用具有合适多靶点特性的单一药物或联合用药抑制两种或更多致癌信号通路（包括Hh信号通路），似乎有望使患者获得临床疗效，并随着特定SMO拮抗剂的长期使用减少耐药性的产生。此外，为了研究新治疗方法的效果，纳入标准应更具特异性，以便选择经检测证实Hh信号通路活性异常的患者。这些考虑对于选择合适的患者和药物以获得最佳治疗效果将非常有帮助。
