Targeting the BDNF/TrkB pathway for the treatment of tumors (Review)
Lingbin Meng, Baoqiong Liu, Rui Ji, Xin Mei Jiang, Xuebo Yan, Ying Xin · 2018 · 77 citationsRead the paper
Neurotrophins are a family of growth factors that regulate neural survival, development, function and plasticity in the central and the peripheral nervous system. There are four neurotrophins: nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and NT-4. Among them, BDNF is the most studied due to its high expression in the brain. Over the past two decades, BDNF and its receptor tropomyosin receptor kinase B (TrkB) have been reported to be upregulated in a wide range of tumors. This activated signal stimulates a series of downstream pathways, including phosphoinositide 3-kinase/protein kinase B, Ras-Raf-mitogen activated protein kinase kinase-extracellular signal-regulated kinases, the phospholipase-C-γ pathway and the transactivation of epidermal growth factor receptor. Activation of these signaling pathways induces oncogenic effects by increasing cancer cell growth, proliferation, survival, migration and epithelial to mesenchymal transition, and decreasing anoikis, relapse and chemotherapeutic sensitivity. The present review summarizes recent findings to discuss the role of BDNF in tumors, the underlying molecular mechanism, targeting Trk receptors for treatment of cancers and its potential risk.
What the full text shows
Deployed in practice- BDNF and TrkB are upregulated in various cancers, promoting growth, proliferation, survival, migration, and epithelial-to-mesenchymal transition. (Breast, lung, colon-rectum, pancreas, prostate, liver, myelomas, and lymphoid tumors)
- Trk receptor inhibitors (Entrectinib, Larotrectinib, Cabozaninib) improve objective response rate, median progression-free survival, and overall survival. (Clinical trials for cancer treatment)
- BDNF rescues neuroblastoma cells from etoposide via the PI3K pathway, but not the MAPK pathway. (Neuroblastoma cells treated with etoposide)
- Larotrectinib causes central nervous system toxicity. (Clinical use)
- Ampakines elevate BDNF levels and correct age-related memory issues. (Brain regions in aging models)
- Setup
- Review of multiple studies including clinical trials of Entrectinib, Larotrectinib, and Cabozaninib.
- How
- Literature review summarizing existing research on the BDNF/TrkB pathway, its downstream signaling (PI3K/Akt, Ras-Raf-MEK-ERK, PLCγ, EGFR), and clinical trial outcomes of Trk inhibitors.
- Limitations
- Trk inhibitors cross the blood-brain barrier, potentially causing CNS toxicity. · Trk inhibitors may attenuate BDNF-mediated anti-cancer immune responses in the hypothalamus. · The role of the p75 receptor in tumors is contradictory (both oncogenic and oncolytic).
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