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Towards Precision Oncology: The Role of Smoothened and Its Variants in Cancer
Alina Nicheperovich1, Andrea Townsend-Nicholson1
1Institute of Structural and Molecular Biology, Research Department of Structural and Molecular Biology, Division of Biosciences, University College London, London WC1E 6BT, UK.
Abstract:
The G protein-coupled receptor Smoothened (Smo) is a central signal transducer of the Hedgehog (Hh) pathway which has been linked to diverse forms of tumours. Stimulated by advancements in structural and functional characterisation, the Smo receptor has been recognised as an important therapeutic target in Hh-driven cancers, and several Smo inhibitors have now been approved for cancer therapy. This receptor is also known to be an oncoprotein itself and its gain-of-function variants have been associated with skin, brain, and liver cancers. According to the COSMIC database, oncogenic mutations of Smo have been identified in various other tumours, although their oncogenic effect remains unknown in these tissues. Drug resistance is a common challenge in cancer therapies targeting Smo, and data analysis shows that healthy individuals also harbour resistance mutations. Based on the importance of Smo in cancer progression and the high incidence of resistance towards Smo inhibitors, this review suggests that detection of Smo variants through tumour profiling could lead to increased precision and improved outcomes of anti-cancer treatments.
Insights
The Smoothened (Smo) receptor is crucial in Hedgehog pathway signaling and cancer. Detecting Smo variants via tumor profiling can improve precision cancer therapy and overcome drug resistance.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The G protein-coupled receptor Smoothened (Smo) is a key transducer in the Hedgehog (Hh) pathway, implicated in various cancers.
- Smo acts as an oncoprotein, with gain-of-function mutations linked to skin, brain, and liver cancers.
- Oncogenic Smo mutations are found in other tumors, but their roles are often uncharacterized.
Purpose of the Study:
- To review the role of Smo in cancer progression.
- To highlight Smo as a therapeutic target in Hh-driven cancers.
- To discuss the challenge of drug resistance in Smo-targeted therapies.
Main Methods:
- Literature review of Smo's role in cancer.
- Analysis of Smo inhibitors and their therapeutic applications.
- Examination of Smo mutations and drug resistance mechanisms.
Main Results:
- Several Smo inhibitors are approved for cancer therapy.
- Drug resistance to Smo inhibitors is a significant clinical challenge.
- Resistance mutations in Smo are also found in healthy individuals.
Conclusions:
- Tumor profiling for Smo variants can enhance precision cancer medicine.
- Detecting Smo variants may improve treatment outcomes for Hh-driven cancers.
- Understanding Smo's role and resistance mechanisms is vital for effective cancer therapy.
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