Trk Signaling Inhibition Reduces cSCC Growth and Invasion in In Vitro and Zebrafish Models and Enhances Photodynamic Therapy Outcome

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer, with a rising global incidence. Neurotrophins (NTs) and their receptors, including TrkA and CD271, play key roles in epidermal homeostasis and tumor progression. We showed that CD271 expression and function are critical for low- to high-risk progression of cSCC, while TrkA is highly expressed in poorly differentiated tumors. Although NTRK fusions are recognized as oncogenic drivers, the functional impact of TrkA signaling in cSCC remains underexplored. In this study, we investigated the effects of TrkA inhibition, using both the pan-Trk inhibitor K252a and siRNA-mediated silencing, on cSCC cell lines. We evaluated cell growth and invasion in vitro, using 2D and 3D cultures, and in vivo using zebrafish xenografts. TrkA inhibition significantly reduced tumor growth and invasion, with efficacy comparable to standard chemotherapeutics (5-FU, cisplatin). Additionally, TrkA blockade downregulated mitogenic and invasive markers. Importantly, TrkA inhibition enhanced the response to photodynamic therapy in cSCC spheroids. In zebrafish, Trk-targeted interventions reduced metastatic dissemination. These findings highlight TrkA as a key regulator of cSCC survival and metastasis, suggesting its potential as a therapeutic target either alone or in combination with existing treatments.