PTRF Confers Melanoma‐Acquired Drug Resistance Through the Upregulation of EGFR

ABSTRACT Melanoma is the most serious type of skin cancer. About half of all melanomas have activating BRAF mutations. Targeted therapy for malignant melanoma with BRAF inhibitor (BRAFi) or its combination with MEK inhibitor (MEKi) improves the clinical outcomes of patients, but resistance develops invariably. The underlying mechanisms remain incompletely understood. Here, we show that caveolae number is increased in both BRAFi and BRAFi + MEKi‐resistant melanoma cells, and the expression of the critical caveolae component PTRF is significantly upregulated in drug‐resistant melanoma cell lines and tumour tissues. Knockdown of PTRF in drug‐resistant cells reduces proliferation with increased apoptosis, whereas ectopic expression of PTRF confers resistance on parental cells to BRAFi or BRAFi + MEKi. On the contrary, the knockdown of PTRF in parental cells reduces their ability to acquire drug resistance induced by BRAFi treatment. Interestingly, we find that the expression of EGFR is increased along with PTRF and caveolin‐1 in drug‐resistant cells and in PTRF transduced parental cells, whereas knockdown of PTRF results in down‐regulation of EGFR expression and attenuates drug resistance of parental cells induced by PTRF expression. Together, these results suggest that PTRF contributes to therapy resistance through upregulating EGFR in melanoma cells.