Identification of anaplastic lymphoma kinase as a potential therapeutic target in Basal Cell Carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Dermatology

Background:

• Basal cell carcinoma (BCC) pathogenesis involves sonic hedgehog (SHH) signaling.
• Current treatments like vismodegib have limited efficacy, necessitating new therapeutic approaches.

Purpose of the Study:

• To identify novel therapeutic targets in BCC by analyzing tumor-specific receptor tyrosine kinase expression.
• To investigate the role of anaplastic lymphoma kinase (ALK) in BCC development and its potential as a therapeutic target.

Main Methods:

• Gene expression profiling of BCC tumor tissues and laser capture microdissection.
• Quantitative reverse transcription PCR (qRT-PCR) and immunohistochemistry to confirm gene expression and protein activity.
• In vitro studies using cultured keratinocytes treated with ALK inhibitor (crizotinib) and c-Met inhibitor.

Main Results:

• A significant >250-fold increase in anaplastic lymphoma kinase (ALK) and its ligands was observed in BCC compared to normal epidermis.
• Crizotinib, an FDA-approved ALK inhibitor, reduced keratinocyte proliferation and significantly decreased SHH-pathway target gene expression (GLI1 and CCND2).
• Phosphorylated ALK expression was notably higher in BCC tumor nests.

Conclusions:

• Anaplastic lymphoma kinase (ALK) may promote keratinocyte proliferation in BCC by upregulating GLI1 expression, potentially in parallel with the SHH pathway.
• Targeting ALK, alone or in combination with SHH pathway inhibitors, represents a promising therapeutic strategy for BCC.