Cabozantinib Is Effective in Melanoma Brain Metastasis Cell Lines and Affects Key Signaling Pathways

Abstract

Melanomas have a high potential to metastasize to the brain. Recent advances in targeted therapies and immunotherapies have changed the therapeutical landscape of extracranial melanomas. However, few patients with melanoma brain metastasis (MBM) respond effectively to these treatments and new therapeutic strategies are needed. Cabozantinib is a receptor tyrosine kinase (RTK) inhibitor, already approved for the treatment of non-skin-related cancers. The drug targets several of the proteins that are known to be dysregulated in melanomas. The anti-tumor activity of cabozantinib was investigated using three human MBM cell lines. Cabozantinib treatment decreased the viability of all cell lines both when grown in monolayer cultures and as tumor spheroids. The in vitro cell migration was also inhibited and apoptosis was induced by cabozantinib. The phosphorylated RTKs p-PDGF-Rα, p-IGF-1R, p-MERTK and p-DDR1 were found to be downregulated in the p-RTK array of the MBM cells after cabozantinib treatment. Western blot validated these results and showed that cabozantinib treatment inhibited p-Akt and p-MEK 1/2. Further investigations are warranted to elucidate the therapeutic potential of cabozantinib for patients with MBM.

Therapeutic targeting of anoikis resistance in cutaneous melanoma metastasis

“…It was first registered by the FDA (2012) for the treatment of patients with progressive and unresectable advanced medullary thyroid cancer (MTC), and has subsequently received FDA registration for use in Frontiers in Cell and Developmental Biology frontiersin.org treatment-refractory advanced renal cell carcinoma (2016), hepatocellular carcinoma (HCC) (2019), and as a first line treatment for differentiated thyroid cancer (DTC) (2021) and RCC (2021). A preclinical study investigating cabozantinib treatment of cell lines derived from melanoma brain metastases demonstrated the ability of the inhibitor to significantly reduce viability of cells in monolayer and 3D spheroid cultures, reduce migration and colony formation, and downregulate phosphorylation of Akt and MEK1/2 (Mannsåker et al, 2021). Phase I and II trials investigating the response of uveal and cutaneous melanoma patients to cabozantinib treatment have been completed [NCT01709435, NCT00940225 (Daud et al, 2017), NCT01835145 (Luke et al, 2020)].…”

A Review of Recurrent Meningiomas with Prolonged Response to Cabozantinib, an Oral Multitarget Tyrosine Kinase Inhibitor

“…Cabozantinib's anti-tumor effects are also aided by the suppression of MET activation-related downstream signaling pathways [80]. This incorporates the restraint of the PI3K/AKT/mTOR pathway, which is basic for cell endurance and multiplication, as well as the MAPK/ERK pathway, which directs cell development and movement [81].Cabozantinib effectively blocks MET signaling through these mechanisms, reducing tumor cell survival, invasion, and metastasis. Cabozantinib's inhibition of MET, in addition to its inhibition of VEGFR, provides a comprehensive strategy for preventing tumor progression and metastasis [82][83].…”

A Review of Recurrent Meningiomas with Prolonged Response to Cabozantinib, an Oral Multitarget Tyrosine Kinase Inhibitor

“…Cabozantinib's anti-tumor effects are also aided by the suppression of MET activation-related downstream signaling pathways [80]. This incorporates the restraint of the PI3K/AKT/mTOR pathway, which is basic for cell endurance and multiplication, as well as the MAPK/ERK pathway, which directs cell development and movement [81].Cabozantinib effectively blocks MET signaling through these mechanisms, reducing tumor cell survival, invasion, and metastasis. Cabozantinib's inhibition of MET, in addition to its inhibition of VEGFR, provides a comprehensive strategy for preventing tumor progression and metastasis [82,83].…”