P2, N=16, Active, not recruiting, Verastem, Inc. | Recruiting --> Active, not recruiting

P2, N=57, Active, not recruiting, University Health Network, Toronto | Trial completion date: Dec 2025 --> Sep 2026 | Trial primary completion date: Dec 2024 --> May 2026

P1, N=14, Active, not recruiting, Emory University | Trial completion date: Oct 2026 --> Dec 2027 | Trial primary completion date: Oct 2025 --> Dec 2026

P2, N=41, Not yet recruiting, University of Alabama at Birmingham | Trial completion date: Dec 2031 --> May 2032 | Trial primary completion date: Dec 2030 --> May 2031

P1, N=36, Not yet recruiting, SpringWorks Therapeutics, Inc.

Trametinib is useful in NRAS-driven leptomeningeal melanoma in children, but not sufficient to prevent relapse, and can be helpful in NRAS-driven leptomeningeal dysplasia. It is very helpful symptomatically in BRAF fusion-driven cutaneous disease, where a reduced dose after initial response appears to sustain efficacy and reduce adverse effects.

P2, N=20, Not yet recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2027 --> Feb 2030 | Trial primary completion date: Dec 2027 --> Feb 2030

This exploratory analysis suggests pERK expression and mutation of KRAS/BRAF/NRAS are candidate biomarkers of improved PFS and response to trametinib, respectively.

The cooperative GOG 281/LOGS trial showed that trametinib, an MEK inhibitor (MEKi), was significantly more effective than standard-of-care options (including chemotherapy or hormonal therapy) in increasing progression-free survival (median PFS 13.0 months vs. 7.2 months; hazard ratio 0.48, p < 0.001)...Genomic and multi-omic profiling have revealed actionable vulnerabilities and precision oncology approaches. The advent of biomarker-directed trials, molecular subtyping incorporation, and innovative computational strategies is likely to gradually ameliorate therapy selection and, thereby, finally improve long-term outcomes for patients with this complex disease.

The proteasome inhibitor MG132 confirmed that fisetin accelerates β-catenin and MITF degradation. Additionally, inhibition of the PI3K/AKT pathway by LY294002 or the ERK pathway by PD98059 reversed fisetin's reduction of tyrosinase activity and melanin synthesis, further verifying the participation of these pathways. Computational docking integrated with deep learning-based CNN scoring revealed that fisetin interacts with PKCα, β-catenin, tyrosinase, and TYRP1. Collectively, these findings suggest that fisetin exerts multi-targeted inhibitory effects on melanogenesis, highlighting its potential as a therapeutic and cosmetic agent for hyperpigmentation.

MEK inhibition with trametinib resulted in similar, yet more pronounced effects. Thus, our findings provide novel insights into NRAS-mediated signaling through nanoscale clusters and underscore their potential as therapeutic targets.

P2, N=20, Not yet recruiting, National Cancer Institute (NCI) | Initiation date: Oct 2025 --> Jan 2026