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Background BRAF/MEK inhibitors have improved the outcome in metastatic melanoma (MM) patients harboring a BRAF mutation, but no biomarker predictive of response has been identified. Methods We conducted a retrospective analysis on 264 MM patients that had received first-line targeted therapy with BRAF/MEK inhibitors. Next-generation sequencing (NGS) was performed on tissue biopsies, and samples with > 30% tumor cellularity were included in the study. The impact of BRAF variant allele frequency (BRAF-VAF) on clinical treatment outcomes was analyzed. Results BRAF-VAF was dichotomized using two approaches. (1) The “surv_cutpoint” function identified two different cut-off for progression-free survival (PFS: 44.05%) and overall survival (OS:45.1%). Patients with BRAF-VAF > 44.05% showed a significantly lower PFS (median PFS: 10 months, 95% CI: 7–13 months), compared to patients with BRAF-VAF < 44.05% (median PFS: 13 months, 95% CI: 12–21 months). Moreover, patients with higher VAF (> 45.1%) experienced a lower OS (median OS: 26 months, 95% CI: 19–38 months), compared with patients with VAF < 45.1% (median OS: 29 months, 95% CI: 29–51 months). (2) The ROC analysis significantly predicted PFS but not OS. BRAF-VAF normalized with neoplastic cellularity (nVAF) showed a strong association with both PFS, and OS compared to BRAF-VAF alone. nVAF also emerged as an independent predictor for PFS in the multivariate analysis (HR: 3.88, 95% CI: 1.84–8.20), with a higher nVAF score associated with a 3.88-fold increased risk of progression. Conclusions Our study demonstrated the role of the BRAF-VAF as predictor of response in MM patients treated with BRAF/MEK inhibitors. Moreover, VAF normalization predicts PFS better than BRAF-VAF alone. Highlights The role of BRAF-VAF in predicting response to BRAF/MEK inhibitors therapy in melanoma has not been elucidated yet. In 264 metastatic melanoma patients treated with first-line targeted therapy, high BRAF-VAF values correlated with worse clinical outcomes. This evidence is further strengthened when BRAF-VAF was normalized using neoplastic cellularity (nVAF). BRAF-VAF can be used as predictor of clinical outcomes in metastatic melanoma patients treated with first-line targeted therapy.

Colorectal cancer (CRC) remains a leading cause of cancer-related death worldwide, with resistance to targeted therapies presenting a significant clinical challenge. This study combines computational and experimental methods to identify and validate Antrocin, a natural sesquiterpene lactone, as a potential multi-target inhibitor of the BRAF/MEK/PI3K oncogenic pathway in CRC. Differential gene expression and mutational analyses were performed using public datasets (TCGA, TNMplot, GEPIA2, GSCA, PANDA, and cBioPortal) to assess the prevalence and clinical significance of BRAF, MEK, and PI3K alterations in CRC. In silico molecular docking, using AutoDock Vina, predicted strong binding affinities of Antrocin to BRAF (ΔG = −8.5 kcal/mol), MEK (ΔG = −7.3 kcal/mol), and PI3K (ΔG = −6.9 kcal/mol), comparable to those of FDA-approved inhibitors for BRAF (Dabrafenib), MEK (Trametinib), and PI3K (Alpelisib). Drug-likeness and ADME properties were evaluated via SwissADME and ADMETlab, supporting Antrocin’s potential as a drug candidate. In vitro assays using HCT116 and RKO CRC cell lines validated that Antrocin treatment suppressed cell viability, spheroid formation, and migration, accompanied by reduced expression levels of the oncogenic BRAF/MEK/PI3K signaling pathway. Antrocin-treated tumor-conditioned medium experiments demonstrated Antrocin’s ability to reduce the differentiation of cancer-associated fibroblasts and the polarization of M2 macrophages. Preclinical mouse xenograft experiments demonstrated a delay in tumor growth following treatment with Antrocin. These results suggest that Antrocin, identified through computational screening and validated experimentally, could be a promising multi-target agent to overcome therapy resistance in CRC.