p38 MAPK-dependent phosphorylation of transcription factor SOX2 promotes an adaptive response to BRAF inhibitors in melanoma cells

Despite recent advances in the development of BRAF kinase inhibitors (BRAFi) for BRAF-mutant melanomas, development of resistance remains a major clinical problem. In addition to genetic alterations associated with intrinsic resistance, several adaptive response mechanisms are known to be rapidly acti-vated to allow cell survival in response to treatment, limiting efficacy. A better understanding of the mechanisms driving resistance is urgently needed to improve the success of BRAF-targeted therapies and to make therapeutic intervention more durable. In this study, we identify the mitogen-activated pro-tein kinase (MAPK) p38 as a novel mediator of the adaptive response of melanoma cells to BRAF-targeted therapy. Our findings demonstrate that BRAFi leads to an early increase in p38 activation, which promotes phosphorylation of the tran-scription factor SOX2 at Ser251, enhancing SOX2 stability, nuclear localization, and transcriptional activity. Furthermore, functional studies show that SOX2 depletion increases sensi-tivity of melanoma cells to BRAFi, whereas overexpression of a phosphomimetic SOX2-S251E mutant is sufficient to drive resistance and desensitize melanoma cells to BRAFi in vitro and in a zebrafish xenograft model. We also found that SOX2 phosphorylation at Ser251 confers resistance to BRAFi by binding to the promoter and increasing transcriptional acti-vation of the ATP-binding cassette drug efflux transporter ABCG2. In summary, we unveil a p38/SOX2-mediated mech-anism of adaptive response to BRAFi, which provides pro -survival signals to melanoma cells against the cytotoxic effects of BRAFi prior to acquiring resistance.