Smoothened variants explain the majority of drug resistance in basal cell carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Advanced basal cell carcinomas (BCCs) often develop resistance to Smoothened (SMO) inhibitors.
• The mechanisms driving this acquired resistance remain largely unknown.

Purpose of the Study:

• To identify the molecular mechanisms underlying SMO inhibitor resistance in advanced BCCs.
• To characterize novel SMO mutations and their impact on Hedgehog signaling.
• To explore therapeutic strategies targeting downstream effectors of SMO signaling.

Main Methods:

• Genomic analysis of SMO in resistant BCC samples.
• Functional assays to assess SMO mutant activity and inhibitor sensitivity.
• In vitro studies evaluating the efficacy of downstream inhibitors.

Main Results:

• SMO mutations were identified in 50% of resistant BCC cases.
• Mutations were found in the ligand binding pocket and conferred constitutive activity.
• SMO variants maintained Hedgehog signaling despite SMO inhibitor presence.
• Tumor cells with SMO mutants outcompeted wild-type cells under inhibitor treatment.
• Both SMO mutant classes responded to downstream inhibitors targeting aPKC-ι/λ or GLI2.

Conclusions:

• SMO mutations are a key mechanism of resistance to SMO inhibitors in advanced BCCs.
• Understanding these mutations illuminates critical residues for receptor autoinhibition.
• Targeting downstream pathways like GLI2 offers a promising therapeutic avenue for resistant BCCs.