Chronic sun-damaged (CSD) melanoma represents 10%-20% of cutaneous melanomas and is characterized by infrequent BRAFV600E mutations and high mutational load.
We explore targeting ERK via a distinct site of protein-protein interaction, known as the D-recruitment site (DRS), as an alternative or supplementary mode of ERK pathway inhibition in BRAF-V600Emelanoma.
Potentially, IL-2/IFN might represent a treatment option in patients with active melanoma after established initial treatment with checkpoint inhibitors and BRAF/MEK-targeted therapies.
While the use of BRAF and MEK inhibitors, either as a single agent or in combination, improved efficacy in BRAF-mutant melanoma, initial responses are often followed by relapse due to acquired resistance.
The US Food and Drug Administration approved a liquid biopsy test for EGFR-activating mutations in patients with non-small-cell lung cancer as a companion diagnostic for therapy selection. ctDNA also allows for the identification of mutations selected by treatment such as EGFR T790M in non-small-cell lung cancer. ctDNA can also detect mutations such as KRAS G12V in colorectal cancer and BRAFV600E/V600K in melanoma.
Treatment of melanoma cell lines expressing endogenous AT2R with either AngII or the AT2R-selective agonist Y6AII induces proliferation in serum-free conditions whereas the AT2R-specific antagonists PD123319 and EMA401 inhibit melanoma growth and angiogenesis and potentiate inhibitors of BRAF and MEK in cells with BRAF V600 mutations.
Areas covered: This article outlines the current knowledge of ncRNA involvement in BRAF-mutant melanomas and the development of resistance to targeted/immunotherapies.
Particular attention has been devoted over the last years to unravel mechanisms at the basis of adaptive/non genetic resistance occurring in BRAF mutated melanomas upon treatment with to MAPKi.
Pharmacological inhibition of ATOX1 with a small molecule, DCAC50, decreased the phosphorylation of ERK1/2 and reduced the growth of BRAF mutation-positive melanoma cell lines in a dose-dependent manner.
The most frequent genetic alterations in melanoma are gain-of-function (GOF) mutations in BRAF, which result in RAF-MEK-ERK signaling pathway addiction.
To improve its therapeutic efficacy and overcome drug resistance in advanced melanomas, we synthesized Tris DBA-Pd hyaluronic acid nanoparticles (Tris DBA-Pd HANP) and evaluated them against in vivo xenografts of LM36R, an aggressive BRAF mutant human melanoma resistant to BRAF inhibitors.
Specific mutations of RAF kinases, such as the prevalent BRAF(V600E) mutation in melanoma, or defects in upstream signaling or feedback loops cause decoupled kinase activities which lead to tumorigenesis.
For example, anti-PD-1/PD-L1 therapy combined with MAP kinase inhibition using BRAF inhibitors (BRAFi) and/or MEK inhibitors (MEKi) are in development for treatment of late stage melanomas.