CSNK1A1 phosphorylates ITGB5 to decrease the sensitivity of hepatocellular carcinoma to the multi-target tyrosine kinase inhibitor by disrupting the EPS15/EGFR complex
Oral multi-target tyrosine kinase inhibitors (TKIs), such as sorafenib, suppressing tumor-cell proliferation and tumor angiogenesis have been approved to treat patients with hepatocellular carcinoma (HCC). Of note, only approximately 30% of patients can benefit from TKIs, and this population usually acquires drug resistance within 6 months. Here, we intend to explore the mechanism that associated with the regulating the sensitivity of HCC to TKIs. We revealed that the ITGB5 was abnormally expressed in HCC and contributed to decreasing the sensitivity of TKIs in HCC. Mechanically, the unbiased mass spectrometry analysis by using the ITGB5 antibodies reveals that ITGB5 interacted with EPS15 to prevent the degradation of EGFR in HCC cells, which activated the AKT-mTOR signaling and MAPK pathway to reduce the sensitivity of TKIs in HCC cells. In addition, the mass spectrometry analysis also showed that CSNK1A1 bound with ITGB5 in HCC cells. The further study indicated that ITGB5 increased the protein level of CSNK1A1 through the EGFR-AKT-mTOR pathway in HCC. And the upregulated CSNK1A1 phosphorylate ITGB5 to enhance the interaction between ITGB5 and EPS15 and activate the EGFR in HCC cells. Thus, we identified a positive feedback loop between ITGB5-EPS15-EGFR-CSNK1A1 in HCC cells. This finding provided a theory basis for the future development of therapeutic strategies to improve the anti-HCC efficacy of TKI. Overall design: Comparative gene expression profiling analysis of RNA-seq data for the Huh7 cells after knockdown of ITGB5.