1585 RET proto-oncogene drives cutaneous squamous carcinoma by inhibiting keratinocyte differentiation

RET proto-oncogene is a receptor tyrosine kinase with three neurotrophic ligands: GDNF, ARTN and NRTN. Activation of central in progression multiple human malignancies; however pathway axis not well defined epithelial cancers. Here, we investigated the tumor enabling capacity cutaneous squamous carcinoma (cSCC) evaluated therapeutic effects blockade. IHC qRT-PCR analysis revealed robust activation RET, its ligands- downstream MAPK genes- SPRY4 DUSP6 cSCC head neck cell (HNSC). Treatments specific inhibitor- BLU-667 or house-developed novel inhibitors, effectively suppressed transformation normal skin organoids into invasive epidermal neoplasia enhanced keratinocyte differentiation organotypic epidermis. ablation by CRISPR/Cas9 approach also induced non-transformed organoids. blockade HNSC lines inhibited spheroid formation growth. Strikingly, treatment mice xenograft tumors progression, cells proliferation differentiation. Altogether, these results suggest that required to maintain de-differentiated progenitor-like state which promotes formation. Our findings indicate targeting cancers could be therapeutically beneficial.