Boonyakorn BoonsriKiren Yacqub-UsmanPakpoom ThintharuaKyaw Zwar MyintThannicha Sae-LaoPam CollierChinnawut SuriyonplengsaengNoppadol LarbcharoensubBrinda BalasubramanianSimran VenkatramanIsioma U. EgbuniweDhanwant GomezAbhik MukherjeeSupeecha KumkateTavan JanvilisriAbed M. ZaitounThiti KuakpaetoonRutaiwan TohtongAnna M. GrabowskaDavid O. BatesKanokpan WongprasertQueen's Medical CentreSiam UniversityFaculty of Medicine Ramathibodi Hospital, Mahidol UniversityUniversity of NottinghamMahidol UniversityRajavithi Hospital2022-08-042022-08-042021-04-01Cancer Research and Treatment. Vol.53, No.2 (2021), 457-47020059256159829982-s2.0-85104369484https://repository.li.mahidol.ac.th/handle/20.500.14594/76223Purpose The potential of members of the epidermal growth factor receptor (ErbB) family as drug targets in cholangiocarcinoma (CCA) has not been extensively addressed. Although phase III clinical trials showed no survival benefits of erlotinib in patients with advanced CCA, the outcome of the standard-of-care chemotherapy treatment for CCA, gemcitabine/cisplatin, is discouraging so we determined the effect of other ErbB receptor inhibitors alone or in conjunction with chemotherapy in CCA cells. Materials and Methods ErbB receptor expression was determined in CCA patient tissues by immunohistochemistry and digital-droplet polymerase chain reaction, and in primary cells and cell lines by immunoblot. Effects on cell viability and cell cycle distribution of combination therapy using ErbB inhibitors with chemotherapeutic drugs was carried out in CCA cell lines. 3D culture of primary CCA cells was then adopted to evaluate the drug effect in a setting that more closely resembles in vivo cell environments. Results CCA tumors showed higher expression of all ErbB receptors compared with resection margins. Primary and CCA cell lines had variable expression of erbB receptors. CCA cell lines showed decreased cell viability when treated with chemotherapeutic drugs (gemcitabine and 5-fluorouracil) but also with ErbB inhibitors, particularly afatinib, and with a combination. Sequential treatment of gemcitabine with afatinib was particularly effective. Co-culture of CCA primary cells with cancer-associated fibroblasts decreased sensitivity to chemotherapies, but sensitized to afatinib. Conclusion Afatinib is a potential epidermal growth factor receptor targeted drug for CCA treatment and sequential treatment schedule of gemcitabine and afatinib could be explored in CCA patients.Mahidol UniversityBiochemistry, Genetics and Molecular BiologyMedicineArticleSCOPUS10.4143/CRT.2020.585