METTL3 induces PLX4032 resistance in melanoma by promoting m6A-dependent EGFR translation.

Acquired resistance often limits therapeutic efficacy of the BFAF (V600E) kinase inhibitor PLX4032 in patients with advanced melanoma. Epitranscriptomic modification of mRNAs by N6-methyladenosine (m6A) modification contributes to melanoma pathogenesis; however, its role in acquired PLX4032 resistance remains unexplored. Here, we showed that m6A methyltransferase METTL3 expression is upregulated in A375R cells, a PLX4032-resistant subline of A375 melanoma cells, compared with the parental cells. Moreover, METTL3 increased the m6A modification of epidermal growth factor receptor (EGFR) mRNA in A375R cells, which promoted its translation efficiency. In turn, increased EGFR expression facilitated rebound activation of the RAF/MEK/ERK pathway in A375R cells, inducing PLX4032 resistance. In contrast, knockout of METTL3 in A375R cells reduced EGFR expression and restored PLX4032 sensitivity. PLX4032 treatment following METTL3 knockout induced apoptosis and reduced colony formation in A375R cells and reduced A375R cell-derived tumor growth in BALB/c nude mice. These findings indicate that METTL3 promotes rebound activation of the RAF/MEK/ERK pathway through EGFR upregulation and highlight a critical role for METTL3-induced m6A modification in acquired PLX4032 resistance in melanoma, implicating METTL3 as a potential candidate for targeted chemotherapy.