TrkA Co-Receptors: The Janus Face of TrkA?

SIMPLE SUMMARY: NGF was the first growth factor discovered by Rita Levi Montalcini in 1950. TrkA, its high affinity receptor, is an oncogene that is overexpressed in many cancers. However, targeted therapies against TrkA, in particular kinase inhibitors, have not yet demonstrated efficacy in the context of overexpression. In this review, after describing the state-of-the-art TrkA-targeted therapies, we will elicit the failures of these therapies by focusing on non-genomic resistance. 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.