BRAF V600E;K601Q metastatic melanoma patient-derived organoids and docking analysis to predict the response to targeted therapy.

The V600E mutation in BRAF is associated with increased phosphorylation of Erk1/2 and high sensitivity to BRAFi/MEKi combination in metastatic melanoma. In very few patients, a tandem mutation in BRAF, V600 and K601, causes a different response to BRAFi/MEKi combination. BRAF ^V600E;K601Q patient-derived organoids (PDOs) were generated to investigate targeted therapy efficacy and docking analysis was used to assess BRAF ^V600E;K601Q interactions with Vemurafenib. PDOs were not sensitive to Vemurafenib and Cobimetinib given alone and sensitive to their combination, although not as responsive as BRAF ^V600E PDOs. The docking analysis justified such a result showing that the tandem mutation in BRAF reduced the affinity for Vemurafenib. Tumor analysis showed that BRAF ^V600E;K601Q displayed both increased phosphorylation of Erk1/2 at cytoplasmic level and activation of Notch resistance signaling. This prompted us to inhibit Notch signaling with Nirogacestat, achieving a greater antitumor response and providing PDOs-based evaluation of treatment efficacy in such rare metastatic melanoma.
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