TOP1 modulation during melanoma progression and in adaptative resistance to BRAF and MEK inhibitors

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Melanoma therapy resistance involves genetic, epigenetic, and phenotypic changes.
• Topoisomerase I (TOP1) is a key DNA enzyme and a potential cancer therapeutic target.
• The role of TOP1 in melanoma therapy sensitivity versus resistance remains unclear.

Purpose of the Study:

• To investigate TOP1 expression and its correlation with melanoma invasiveness and therapy resistance.
• To explore the functional role of TOP1 inhibition in different melanoma phenotypes.

Main Methods:

• Analysis of TOP1 expression in melanoma cell lines and patient samples.
• Correlation of TOP1 levels with gene expression signatures related to invasion and MITF (microphthalmia-associated transcription factor).
• Assessment of TOP1 and DNA repair gene expression in BRAF inhibitor (BRAFi)- and BRAF/MEK inhibitor (BRAFi/MEKi)-resistant melanoma cells.
• Evaluation of TOP1 inhibition effects on invasion markers in resistant cells.

Main Results:

• TOP1 expression is increased in metastatic melanoma and linked to invasive gene signatures.
• TOP1 levels are inversely correlated with MITF expression, a melanoma regulator.
• TOP1 and DNA Single-Strand Break Repair genes are downregulated in BRAFi- and BRAFi/MEKi-resistant melanoma.
• TOP1 inhibition reduced invasion markers specifically in BRAFi/MEKi-resistant melanoma cells.

Conclusions:

• Three distinct TOP1-related phenotypes in melanoma progression: non-malignant (low TOP1), metastatic (high TOP1, high invasion), and resistant (low TOP1, high invasion).
• TOP1 plays a significant role in melanoma progression and the development of therapy resistance.
• Targeting TOP1 may offer therapeutic potential, particularly in specific resistant melanoma subtypes.