CD133 Is Associated with Increased Melanoma Cell Survival after Multikinase Inhibition

Area of Science:

• Oncology
• Cancer Biology
• Pharmacology

Background:

• FDA-approved kinase inhibitors, including MEK (trametinib) and BRAF (dabrafenib) inhibitors, are used for melanoma treatment.
• Melanoma recurrence is high due to treatment-resistant subpopulations, potentially cancer stem cells.
• CD133 is a marker associated with cancer stem cells and poorer survival across various cancers.

Purpose of the Study:

• To investigate the role of CD133 in melanoma cell resistance to MAPK inhibitors.
• To determine if CD133(+) melanoma cells exhibit differential sensitivity to trametinib and dabrafenib.
• To elucidate the mechanisms underlying CD133-mediated drug resistance.

Main Methods:

• Patient-derived melanoma cells were separated into CD133(+) and CD133(-) subpopulations.
• Cells were treated with increasing concentrations of trametinib and/or dabrafenib.
• Drug sensitivity was assessed by IC50 values.
• siRNA knockdown, microarray, and qRT-PCR were used to analyze gene expression and functional relationships.

Main Results:

• CD133(+) melanoma cells showed significantly greater resistance (higher IC50s) to MAPK inhibitors compared to CD133(-) cells.
• The percentage of CD133(+) cells increased after high-dose drug treatment in mixed populations.
• siRNA knockdown of CD133 reversed drug resistance.
• Ten of 18 ABC transporter genes were upregulated in CD133(+) cells, and inhibiting ABC activity enhanced drug sensitivity.

Conclusions:

• CD133 expression confers significant resistance to MAPK inhibitors in melanoma.
• Upregulation of ABC transporters in CD133(+) cells contributes to this drug resistance.
• Targeting CD133 or ABC transporter activity may represent novel therapeutic strategies to overcome melanoma treatment resistance.