Abstract
Hedgehog (Hh) signaling is a highly conserved pathway that plays a vital role during embryonic development. Recently, uncontrolled activation of this pathway has been demonstrated in various types of cancer. Therefore, Hh pathway inhibitors have emerged as an important class of anti-cancer agents. Unfortunately, however, their reputation has been tarnished by the emergence of resistance during therapy, necessitating clarification of mechanisms underlying the drug resistance. In this review, we briefly overview canonical and non-canonical Hh pathways and their inhibitors as targeted cancer therapy. In addition, we summarize the mechanisms of resistance to Smoothened (SMO) inhibitors, including point mutations of the drug binding pocket or downstream molecules of SMO, and non-canonical mechanisms to reinforce Hh pathway output. A distinct mechanism involving loss of primary cilia is also described to maintain GLI activity in resistant tumors. Finally, we address the main strategies to circumvent the drug resistance. These strategies include the development of novel and potent inhibitors targeting different components of the canonical Hh pathway or signaling molecules of the non-canonical pathway. Further studies are necessary to avoid emerging resistance to Hh inhibitors and establish an optimal customized regimen with improved therapeutic efficacy to treat various types of cancer, including basal cell carcinoma.
Highlights
The Hedgehog (Hh) signaling pathway plays crucial roles in embryonic development, transmitting information to regulate cell growth and differentiation [1,2,3]
These findings support the model in which activated serum response factor (SRF) and megakaryoblastic leukemia 1 (MKL1) maintain the downstream activity of the Hh pathway and are necessary for resistant tumor growth in basal cell carcinoma (BCC) [131]
The mPEG5kDa-cholane/Glabrescione B (GlaB) micellar system can be properly exploited in the treatment of patients with medulloblastoma, for those tumors showing resistance to SMO inhibitors or harboring GLI1 hyperactivation by SMO-independent mechanisms [159]
Summary
The Hedgehog (Hh) signaling pathway plays crucial roles in embryonic development, transmitting information to regulate cell growth and differentiation [1,2,3]. The Hh signaling pathway has been recognized as one of the most intensely investigated targets for cancer treatment Aberrant activation of this pathway was found in various types of cancer, such as basal cell carcinoma (BCC), medulloblastoma, breast cancer, lung cancer, etc. Numb antagonizes Hh effects on medulloblastoma and cerebellar granule cell progenitors cells by targeting and inhibiting GLI function [46] Another negative regulatory mechanism of GLI activity applies to the Notch pathway, which displays tumor suppressor function in the skin [47]. Type I cancer, the first discovered, harbors Hh pathway-activating mutations and is independent of Hh ligands This autonomous activation occurs in BCC and medulloblastoma [11,59] and results from loss-of-function mutations in PTCH or SUFU, or gain-of-function mutations in SMO [56,62,65,66]. Stromal cells provide a tumor microenvironment that is favorable for tumor growth, and Hh signaling may be a potential therapeutic target for the treatment of these hematological cancers [77]
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