TrkA Co-Receptors: The Janus Face of TrkA?

Abstract

Larotrectinib and Entrectinib are specific pan-Trk tyrosine kinase inhibitors (TKIs) approved by the Food and Drug Administration (FDA) in 2018 for cancers with an NTRK fusion. Despite initial enthusiasm for these compounds, the French agency (HAS) recently reported their lack of efficacy. In addition, primary and secondary resistance to these TKIs has been observed in the absence of other mutations in cancers with an NTRK fusion. Furthermore, when TrkA is overexpressed, it promotes ligand-independent activation, bypassing the TKI. All of these clinical and experimental observations show that genetics does not explain all therapeutic failures. It is therefore necessary to explore new hypotheses to explain these failures. This review summarizes the current status of therapeutic strategies with TrkA inhibitors, focusing on the mechanisms potentially involved in these failures and more specifically on the role of TrkA.

ProNGF promotes brain metastasis through TrkA/EphA2 induced Src activation in triple negative breast cancer cells

“…These two growth factors act through TrkA phosphorylation and underlying signaling pathway [ 14 , 17 ]. However, for the first time, we have shown that NGF and proNGF can also activate TrkA-independent signaling through [ 18 ] the formation of TrkA/CD44v3 [ 11 , 19 ] and TrkA/EphA2 [ 20 ] receptor complexes respectively. Notably, proNGF is the common form of NGF in the brain [ 21 ].…”

A Possible Role for Nerve Growth Factor and Its Receptors in Human Sperm Pathology

“…One member, nerve growth factor (NGF), also exerts a variety of effects on non-neuronal cells [1][2][3][4][5][6]. Non-neuronal cells produce this protein, and several cell types throughout the body may express NGF receptors: the high-affinity tropomyosin receptor kinase A (TrKA), responsible for the activation of signalling pathways that promote cell survival, differentiation and growth, and the low-affinity receptor p75 neurotrophin receptor (p75 NTR ), which is more broadly expressed in various cell types where it modulates cellular responses based on the specific context [7][8][9][10].…”