Her2 crosstalks with TrkA in a subset of prostate cancer cells: Rationale for a guided dual treatment

BACKGROUND. To date, no effective therapeutic treatment prevents prostate cancer (PCa) progression to more advanced and invasive disease forms. It has been demonstrated that the simultaneous high expression of p185HER2 and TrkA might confer a proliferative advantage to PCa cells. METHODS. In this work we verified the crosstalk between TrkA and Her2 signaling pathways and the effects of a combined treatment with Her2 and TrkA inhibitors. RESULTS. NGF induced TrkA activation and stimulated cell proliferation of PCa cells. NGF induced also tyrosine phosphorylation of p185HER2. This event was only partially inhibited by the pan Trk inhibitor, CEP-701 but was strongly blocked by pertuzumab, a humanized antibody blocking Her2 heterodimerization. In presence of NGF, TrkA and Her2 co-precipitated and this was dependent to the relative high cellular levels of TrkA since when cell lysates were immunoprecipitated with an antibody against Her2 the amount of TrkA were proportional to the cellular levels of this receptor. On the contrary when we immunoprecipitated using an antibody against TrkA the amount of Her2 seemed independent to cellular levels of Her2. So, combined treatment between CEP-701 and pertuzumab showed supra-additive effects in cells with higher levels of TrkA and Her2 suggesting once again that this was indicative of a higher response to treatment. CONCLUSIONS. Our data suggest that the dual inhibition of TrkA and Her2 may be useful in a subset of patients in which TrkA and Her2 are overexpressed and in which the possibility of TrkA and Her2 protein-binding is elevated.