N6-methyladenosine–mediated up-regulation of ARRB2 regulates intrahepatic cholangiocarcinoma malignant progression and pemigatinib resistance through MAPK and Hippo signaling pathways

Intrahepatic cholangiocarcinoma (ICC) is a major contributor to cancer-related mortality on a global scale, yet it suffers from a lack of reliable early diagnostic biomarkers and effective therapeutic targets. Pemigatinib has been identified as a therapeutic option for advanced ICC; however, its long-term clinical efficacy is significantly hindered by the development of drug resistance. To address this, pemigatinib-resistant ICC cells were established by culturing with increasing drug treatment. 98 pairs of ICC tissue samples were collected and analyzed to assess the association between β-arrestin 2 (ARRB2) and ICC progression. The role and mechanism of ARRB2 in the malignant progression of ICC and resistance to pemigatinib were explored in vitro and in vivo experiments. The results demonstrated that ARRB2 expression is markedly upregulated in pemigatinib-resistant ICC cells compared to their parental counterparts. Suppression of ARRB2 expression markedly attenuated ICC chemoresistance to pemigatinib. Clinical data further verified that ARRB2 is correlated with poorer pathological stage and prognosis in ICC patients. Mechanistic studies revealed that ARRB2 activation in ICC is mediated by METTL3-dependent m6A methylation. Functional analyses demonstrated that ARRB2 promotes the malignant progression of ICC by facilitating YAP nuclear translocation while also modulating the sensitivity of ICC to pemigatinib through the Raf-MEK-ERK signaling axis. This study identifies the tumor-promoting activities of ARRB2 and elucidates the regulatory mechanism of the METTL3-ARRB2-YAP/Raf axis in ICC, which may provide a novel prognostic biomarker and potential therapeutic target for human ICC.