Targeted therapies

In melanoma, alterations in signaling pathways such as MAPK and PI3K often lead to therapy resistance, as inhibition of one pathway can activate compensatory mechanisms. Despite recent advances, resistance and relapse in melanoma brain metastases (MBM) remain major clinical challenges.

Published: (Updated: )

CCT196969
The pan-RAF and SRC inhibitor 196969 effectively inhibits MBM cell viability when grown as monolayer cultures (top row) or multicellular spheroids (middle ro). Migration is also effectively inhibited (bottom row). Photo: Frits Thorsen, Department of Biomedicine, UiB

CCT196969 (external link), a dual SRC family kinase (SFK) and RAF inhibitor, has shown potent anti-tumor effects in primary melanoma models. We evaluated its activity in multiple MBM cell lines, where it consistently inhibited proliferation, migration, and survival. Treatment reduced the expression of p-ERK, p-MEK, p-STAT3, and STAT3, and also suppressed growth in BRAF inhibitor-resistant melanoma cell lines.

Cabozantinib (external link), a receptor tyrosine kinase (RTK) inhibitor approved for non-cutaneous cancers, was also tested in three human MBM cell lines. It reduced cell viability in both monolayer and spheroid cultures, inhibited migration, and induced apoptosis. Phosphorylation of RTKs including PDGF-Rα, IGF-1R, MERTK, and DDR1 was decreased, as confirmed by p-RTK array and Western blot analyses. Additionally, cabozantinib suppressed p-Akt and p-MEK1/2 signaling.