SRS198 - Cracking the Code: Kidins220's loss fuels IGF-1R/IGF1-driven pancreatic cancer progression and metastasis—offering a biomarker to guide surgery and targeted therapy

Abstract Introduction Kidins220, a transmembrane scaffold protein, has been implicated in the biology of several cancers. In pancreatic cancer, we observed reduced Kidins220 expression, which correlated with poor overall survival and distant metastases. Functional studies demonstrated that Kidins220 knockdown enhanced invasiveness through EGFR and MMP upregulation. However, the underlying mechanisms, particularly the contribution of other receptor tyrosine kinases (RTKs), remain unclear. This study aimed to explore the role of insulin-like growth factor receptor (IGF-1R)/IGF1 in Kidins220-associated invasion and progression. Materials and Methods Pancreatic cancer cell lines (MiaPaCa-2, PANC-1, and AsPc-1) from ATCC were subjected to lentiviral knockdown of Kidins220, with scrambled as a control. Publicly available clinical datasets (TCGA, GSE71729, GSE15471) were interrogated to compare tumour versus normal expression. Knockdown efficiency and RTK signalling alterations were assessed by PCR, western blotting, IHC and using small inhibitors. Results and Discussion Kidins220 knockdown was confirmed in pancreatic cancer cells. Among RTKs examined (PDGFRB, HER2, IGF-1R), IGF-1R showed consistent upregulation in Kidins220-deficient MiaPaCa-2, PANC-1, and AsPc-1 cells, accompanied by activation of downstream signalling. Clinical dataset analysis supported these findings, revealing significant correlations between reduced Kidins220 and increased RTK activity, particularly IGF-1R. Correlation heatmaps further suggested a broader Kidins220 RTK regulatory network involved in disease progression. These results highlight IGF-1R as a critical mediator of aggressive behaviour in Kidins220-low pancreatic cancers. Conclusions Loss of Kidins220 induces IGF-1R upregulation and signalling, driving pancreatic cancer aggressiveness. Targeting IGF-1R in patients with reduced Kidins220 expression may represent a novel therapeutic strategy and merits further mechanistic and translational evaluation.