Il ruolo delle varianti di splicing di TrkA nei tumori

Alternative splicing of the NTRK1/TrkA gene leads to the expression of the oncogenic TrkAIII variant, first identified in pediatric neuroblastoma, where it is linked to post-therapeutic relapse and metastasis. TrkAIII mRNA skips exons 6 and 7, preventing cell surface expression and causing accumulation in pre-Golgi membranes, centrosomes, and mitochondria, where it undergoes stress-regulated, ligand-independent activation. Its oncogenic activity involves PI3K-AKT signaling, chromosomal instability, stem-like phenotype maintenance, and mitochondrial protection. Trk inhibitors Entrectinib and Lestaurtinib block TrkAIII activation, highlighting its potential as a therapeutic target. TrkAIII splicing is promoted by oncogenic SV40 polyomavirus large T antigen and tumor microenvironmental stressors like hypoxia, nutrient deprivation, and ER stress, and is present in Merkel cell carcinomas (MCCs), both MCPyV-positive and -negative. This study extends TrkAIII analysis to cutaneous malignant melanomas (CMMs) and pituitary neuroendocrine tumors (PitNETs). In CMMs, TrkAIII splicing was more frequent in metastatic tumors and associated with intracellular TrkA phosphorylation and ER stress-driven unconventional Xbp-1 splicing. In BRAF(V600E)-mutated A375 melanoma cells, ER stress induced TrkAIII expression, increasing resistance to cytotoxicity, which was reversed by Trk inhibitors. In PitNETs, alternative TrkAIII splicing was most prominent in invasive PIT1 tumors and correlated with HIF-2α expression and TrkA phosphorylation, suggesting a link to hypoxia response activation. TrkAIII was also implicated in PD-L1-mediated immune evasion, as TrkAIII-expressing neuroblastoma cells showed increased PD-L1 expression, suppressed Jurkat IL-2 production, and PI3K-dependent immune modulation, reversible by Entrectinib and PI3K inhibition. These findings establish TrkAIII alternative splicing as a key oncogenic mechanism in CMMs and PitNETs, alongside neuroblastomas and MCCs, and reveal a role in PD-L1 upregulation. They also provide a rationale for extending Trk inhibitor therapy to metastatic, therapy-resistant CMMs and PitNETs driven by TrkAIII.