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Non-Canonical Hh Signaling in Cancer-Current Understanding and Future Directions
1Departments of Pediatrics, Biochemistry and Molecular Biology, Pharmacology and Toxicology, The Wells Center for Pediatrics Research, 1044 W, Walnut Street, Indianapolis, IN 46202, USA. donggu@iu.edu.
Abstract:
As a major regulatory pathway for embryonic development and tissue patterning, hedgehog signaling is not active in most adult tissues, but is reactivated in a number of human cancer types. A major milestone in hedgehog signaling in cancer is the Food and Drug Administration (FDA) approval of a smoothened inhibitor Vismodegib for treatment of basal cell carcinomas. Vismodegib can block ligand-mediated hedgehog signaling, but numerous additional clinical trials have failed to show significant improvements in cancer patients. Amounting evidence indicate that ligand-independent hedgehog signaling plays an essential role in cancer. Ligand-independent hedgehog signaling, also named non-canonical hedgehog signaling, generally is not sensitive to smoothened inhibitors. What we know about non-canonical hedgehog signaling in cancer, and how should we prevent its activation? In this review, we will summarize recent development of non-canonical hedgehog signaling in cancer, and will discuss potential ways to prevent this type of hedgehog signaling.
Insights
Hedgehog signaling, crucial in development, reactivates in cancers. Non-canonical hedgehog signaling, insensitive to current drugs like Vismodegib, is a key focus for future cancer therapies.
Area of Science:
- Oncology
- Molecular Biology
- Developmental Biology
Background:
- Hedgehog signaling is vital for embryonic development but typically inactive in adult tissues.
- Reactivation of hedgehog signaling is observed in various human cancers.
- The FDA-approved drug Vismodegib targets ligand-mediated hedgehog signaling in basal cell carcinoma.
Purpose of the Study:
- To review recent advancements in understanding non-canonical hedgehog signaling in cancer.
- To discuss strategies for preventing the activation of non-canonical hedgehog signaling in cancer.
Main Methods:
- Literature review of recent studies on non-canonical hedgehog signaling.
- Analysis of clinical trial data regarding hedgehog signaling inhibitors.
- Synthesis of current knowledge on cancer-associated hedgehog signaling pathways.
Main Results:
- Ligand-independent (non-canonical) hedgehog signaling plays a significant role in cancer progression.
- Non-canonical hedgehog signaling pathways are generally resistant to smoothened inhibitors like Vismodegib.
- Clinical trials with existing inhibitors have shown limited success, highlighting the need for new therapeutic targets.
Conclusions:
- Non-canonical hedgehog signaling represents a critical, yet poorly understood, mechanism in cancer.
- Targeting non-canonical hedgehog signaling pathways is essential for developing more effective cancer treatments.
- Further research into the activation mechanisms and therapeutic inhibition of non-canonical hedgehog signaling is warranted.
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