2. Academic Validation
  3. p38 MAPK-dependent phosphorylation of transcription factor SOX2 promotes an adaptive response to BRAF inhibitors in melanoma cells

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

  • J Biol Chem. 2022 Sep;298(9):102353. doi: 10.1016/j.jbc.2022.102353.
Silvia Pietrobono 1,  Raffaella De Paolo 2,  Domenico Mangiameli 3,  Andrea Marranci 4,  Ilaria Battisti 5,  Cinzia Franchin 5,  Giorgio Arrigoni 5,  Davide Melisi 6,  Laura Poliseno 4,  Barbara Stecca 7
Affiliations

Affiliations

  • 1 Core Research Laboratory, Institute for Cancer Research and Prevention (CRL-ISPRO), Florence, Italy; Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy. Electronic address: silvia.pietrobono@univr.it.
  • 2 Oncogenomics Unit, CRL-ISPRO, Pisa, Italy; Institute of Clinical Physiology, CNR, Pisa, Italy; Department of Medical Biotechnologies, University of Siena, Siena, Italy.
  • 3 Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy.
  • 4 Oncogenomics Unit, CRL-ISPRO, Pisa, Italy; Institute of Clinical Physiology, CNR, Pisa, Italy.
  • 5 Proteomics Center, University of Padova and Azienda Ospedaliera di Padova, Padova, Italy; Department of Biomedical Sciences, University of Padova, Padova, Italy.
  • 6 Digestive Molecular Clinical Oncology Research Unit, University of Verona, Verona, Italy; Experimental Cancer Medicine Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy.
  • 7 Core Research Laboratory, Institute for Cancer Research and Prevention (CRL-ISPRO), Florence, Italy. Electronic address: b.stecca@ispro.toscana.it.
PMID: 35944584 DOI: 10.1016/j.jbc.2022.102353
Abstract

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 activated 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 protein 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 transcription factor SOX2 at Ser251, enhancing SOX2 stability, nuclear localization, and transcriptional activity. Furthermore, functional studies show that SOX2 depletion increases sensitivity 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 activation of the ATP-binding cassette drug efflux transporter ABCG2. In summary, we unveil a p38/SOX2-mediated mechanism of adaptive response to BRAFi, which provides prosurvival signals to melanoma cells against the cytotoxic effects of BRAFi prior to acquiring resistance.

Keywords

BRAF inhibitor; SOX2; drug resistance; p38 MAPK.

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