Direct Targeting of the Raf-MEK-ERK Signaling Cascade Inhibits Neuroblastoma Growth

Abstract

The Raf-MEK-ERK signaling network has been the subject of intense research due to its role in the development of human cancers, including pediatric neuroblastoma (NB). MEK and ERK are the central components of this signaling pathway and are attractive targets for cancer therapy. Approximately 3–5% of the primary NB samples and about 80% of relapsed samples contain mutations in the Raf-MEK-ERK pathway. In the present study, we analyzed the NB patient datasets and revealed that high RAF and MEK expression leads to poor overall survival and directly correlates with cancer progression and relapse. Further, we repurposed a specific small-molecule MEK inhibitor CI-1040 to inhibit the Raf-MEK-ERK pathway in NB. Our results show that CI-1040 potently inhibits NB cell proliferation and clonogenic growth in a dose-dependent manner. Inhibition of the Raf-MEK-ERK pathway by CI-1040 significantly enhances apoptosis, blocks cell cycle progression at the S phase, inhibits expression of the cell cycle-related genes, and significantly inhibits phosphorylation and activation of the ERK1/2 protein. Furthermore, CI-1040 significantly inhibits tumor growth in different NB 3D spheroidal tumor models in a dose-dependent manner and by directly inhibiting spheroidal tumor cells. Overall, our findings highlight that direct inhibition of the Raf-MEK-ERK pathway is a novel therapeutic approach for NB, and further developing repurposing strategies using CI-1040 is a clinically tractable strategy for effectively treating NB.

Targeting Cell Signaling Pathways in Lung Cancer by Bioactive Phytocompounds

“…Downstream signaling cascades include the PI3K/Akt/mTOR pathway; RAS/RAF/MEK/ERK pathway [48]; and Ras-like (Ral) guanine nucleotide exchange factors (GEFs)/Ral [49]. Upon binding of growth factors to their respective receptors, RAS is activated with the aid of the growth factor receptor-bound protein 2 (Grb2)/son of sevenless (SOS) coupling complex [50]. RAS then undergoes a conformational change, binds GTP, and further recruits RAF (A-RAF, B-RAF, or RAF-1).…”

Investigating the effect of MAP2K1 gene (MEK1) in MAPK pathway in the induction of adult T-cell leukemia/lymphoma (ATLL)

“…Specifically, mutations in RAF and RAS proteins cause improper activation of MAPK pathways, and as a result, constitutive activation occurs in the extracellular signal-regulated protein kinase 1/2 (ERK1/2) pathway ( 15 ). In various cancers, including thyroid, neuroblastoma, breast, and non-small cell lung cancer, the MAPK pathway has been identified as a primary cell signaling pathway ( 16 ). The MEK1 protein kinase is made by providing instructions from the MAP2K1 gene.…”