Hedgehog pathway inhibitors, also sometimes called hedgehog inhibitors, are small molecules that inhibit the activity of a component of the Hedgehog signaling pathway. Due to the role of aberrant Hedgehog signaling in tumor progression and cancer stem cell maintenance across cancer types, inhibition of the Hedgehog signaling pathway can be a useful strategy for restricting tumor growth and for preventing the recurrence of the disease post-surgery, post-radiotherapy, or post-chemotherapy. Thus, Hedgehog pathway inhibitors are an important class of anti-cancer drugs. At least three Hedgehog pathway inhibitors have been approved by the Food and Drug Administration (FDA) for cancer treatment. These include vismodegib and sonidegib, both inhibitors of Smoothened (SMO), which are being used for the treatment of basal cell carcinoma. Arsenic trioxide, an inhibitor of GLI transcription factors, is being used for the treatment of acute promyelocytic leukemia. In addition, multiple other Hedgehog pathway inhibitors are in different phases of clinical trials.
Overview of the Hedgehog signaling pathway The classical Hedgehog signaling pathway involves glycoproteins that are secreted by cells into the intercellular space. Multiple such glycoproteins have been characterized: Sonic Hedgehog (Shh), Indian Hedgehog (Ihh), and Desert Hedgehog (Dhh). Among these, Shh is the most potent. It binds and inactivates the transmembrane protein Patched1 (PTCH1). In the absence of Shh, PTCH1 inhibits the activity of Smoothened (SMO), another transmembrane protein. Upon the inactivation of PTCH1 by Shh, glioma-associated (GLI) transcription factors enter the nucleus and activate the expression of multiple genes including Myc, Bcl-2, NANOG, and SOX2. Targets of GLIs include genes involved in cell proliferation, apoptosis, angiogenesis, epithelial-mesenchymal transition, and self-renewal of stem cells. In addition to the canonical pathway described above, some alternate pathways related to Shh signaling have also been reported. One example is the activation of SMO without the subsequent entry of GLI transcription factors into the nucleus. Another, better characterized pathway is the activation of GLIs independent of Shh or PTCH1 / SMO. This alternate mode of triggering the activity of GLIs is common in cancer cells. Oncogenes such as KRAS can activate the GLIs in the absence of Shh signaling. Transcriptional activity of GLIs is also upregulated upon the knockdown of p53, a tumor-suppressor gene often lost during cancer progression.
Role of Hedgehog signaling in cancer As mentioned above, targets of the Hedgehog signaling pathway include genes involved in cell proliferation, apoptosis, angiogenesis, epithelial-mesenchymal transition, and self-renewal of stem cells. Dysregulation of all these cellular processes has been reported across cancer types. Abnormal control of these processes in cancer cells is often a consequence of dysregulated Shh signaling. The first major breakthrough in understanding the role of Shh signaling in cancer progression was the discovery that mutations in the PTCH1 gene, which codes for the PTCH1 protein, were responsible for Gorlin syndrome. Gorlin syndrome is an autosomal dominant disorder characterized by developmental abnormalities and increased risk of developing basal cell carcinoma or medulloblastoma. Mutations in the PTCH1 gene can lead to the abnormal activation of GLI transcriptional activity which in turn promotes tumor development and progression. Overexpression of Shh ligand has been reported in multiple cancer types including pancreatic, colorectal, prostate, and gliomas. This can lead to the activation of GLI transcriptional activity in the cell over-secreting Shh (autocrine signaling) or in neighboring cells (paracrine signaling). Further, Shh ligands can stimulate the production of growth factors by stromal cells present in the tumor microenvironment. These growth factors, in turn, promote the growth, survival, and proliferation of cancer cells. Aberrant Shh signaling has also been implicated in the maintenance of cancer stem cells (CSCs). In chronic myeloid leukemia and breast cancer, inhibition of Shh signaling has been shown to reduce stem cell propagation and renewal. In pancreatic and colorectal cancer, Shh signaling in CSCs drives epithelial-mesenchymal transition and, ultimately, cancer metastasis. CSCs exhibit increased potential for self-renewal, differentiation, and for starting secondary tumors at distant organ sites. CSCs also exhibit mechanisms that drive resistance to chemotherapies and radiotherapy. As a result, while chemotherapy and radiotherapy are often successful in eliminating the bulk of the tumor (which consists of non-CSCs), CSCs that are left behind can lead to tumor recurrence. Thus, via its role in CSC maintenance, Shh signaling contributes towards the failure of anti-cancer therapies.
Mechanism of action Given the role of Shh signaling in promoting tumor progression and in the failure of anti-cancer therapies, the Hedgehog signaling pathway is an important therapeutic target for restricting tumor progression and to prevent disease recurrence post-treatment. Different parts of the Hedgehog signaling pathway may be targeted to abrogate the activation of pathways that promote tumor progression.
SMO Inhibitors Inhibition of the transmembrane protein Smoothened (SMO) prevents the induction of GLI transcriptional activity upon exposure of cancer cells to Shh ligands. Loss of induction of GLIs upon activation of Shh signaling inhibits the ability of Shh signaling to promote tumor progression and cancer stem cell maintenance. Therefore, SMO has been a primary target in the development of Hedgehog pathway inhibitors. Two such inhibitors, Sonidegib and Vismodegib have been approved by the Food and Drug Administration (FDA) for treating basal cell carcinoma. Multiple other SMO inhibitors are in active clinical trials.
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