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Proteasomal down-regulation of the proapoptotic MST2 pathway contributes to BRAF inhibitor resistance in melanoma. | LitMetric

AI Article Synopsis

  • - The RAS-RAF-MEK-ERK pathway is often overactive in malignant melanomas, primarily due to mutations in BRAF or NRAS, with BRAF inhibitors being effective but resistance occurring quickly.
  • - The study found that the mutated BRAF protein binds to and inhibits MST2, a pathway that promotes apoptosis, leading to decreased effectiveness of BRAF inhibitors.
  • - In resistant melanoma cell lines, MST2 proteins are degraded, and increasing their levels with proteasome inhibitors can restore apoptosis, highlighting the MST2 pathway's role in BRAFi resistance.

Article Abstract

The RAS-RAF-MEK-ERK pathway is hyperactivated in most malignant melanomas, and mutations in BRAF or NRAS account for most of these cases. BRAF inhibitors (BRAFi) are highly efficient for treating patients with BRAF mutations, but tumours frequently acquire resistance within a few months. Multiple resistance mechanisms have been identified, due to mutations or network adaptations that revive ERK signalling. We have previously shown that RAF proteins inhibit the MST2 proapoptotic pathway in a kinase-independent fashion. Here, we have investigated the role of the MST2 pathway in mediating resistance to BRAFi. We show that the BRAF mutant protein, but not the wild-type BRAF protein, binds to MST2 inhibiting its proapoptotic signalling. Down-regulation of MST2 reduces BRAFi-induced apoptosis. In BRAFi-resistant cell lines, MST2 pathway proteins are down-regulated by ubiquitination and subsequent proteasomal degradation rendering cells refractory to MST2 pathway-induced apoptosis. Restoration of apoptosis can be achieved by increasing MST2 pathway protein expression using proteasome inhibitors. In summary, we show that the MST2 pathway plays a role in the acquisition of BRAFi resistance in melanoma.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9434705PMC
http://dx.doi.org/10.26508/lsa.202201445DOI Listing

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