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Effect of Combining EGFR Tyrosine Kinase Inhibitors and Cytotoxic Agents on Cholangiocarcinoma Cells

Boonsri, Boonyakorn; Yacqub-Usman, Kiren; Thintharua, Pakpoom; Myint, Kyaw Zwar; Sae-Lao, Thannicha; Collier, Pam; Suriyonplengsaeng, Chinnawut; Larbcharoensub, Noppadol; Balasubramanian, Brinda; Venkatraman, Simran; Egbuniwe, Isioma U.; Gomez, Dhanwant; Mukherjee, Abhik; Kumkate, Supeecha; Janvilisri, Tavan; Zaitoun, Abed M; Kuakpaetoon, Thiti; Tohtong, Rutaiwan; Grabowska, Anna M.; Bates, David O.; Wongprasert, Kanokpan


Boonyakorn Boonsri

Kiren Yacqub-Usman

Pakpoom Thintharua

Kyaw Zwar Myint

Thannicha Sae-Lao

Pam Collier

Chinnawut Suriyonplengsaeng

Noppadol Larbcharoensub

Brinda Balasubramanian

Simran Venkatraman

Dhanwant Gomez

Supeecha Kumkate

Tavan Janvilisri

Abed M Zaitoun

Thiti Kuakpaetoon

Rutaiwan Tohtong

Professor of Cancer Microenvironment

Kanokpan Wongprasert


Purpose 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.


Boonsri, B., Yacqub-Usman, K., Thintharua, P., Myint, K. Z., Sae-Lao, T., Collier, P., …Wongprasert, K. (2020). Effect of Combining EGFR Tyrosine Kinase Inhibitors and Cytotoxic Agents on Cholangiocarcinoma Cells. Cancer Research and Treatment, 53(2), 457-470.

Journal Article Type Article
Acceptance Date Oct 5, 2020
Online Publication Date Oct 7, 2020
Publication Date Oct 7, 2020
Deposit Date Feb 3, 2021
Publicly Available Date Feb 8, 2021
Journal Cancer Research and Treatment
Electronic ISSN 2005-9256
Publisher Korean Cancer Association
Peer Reviewed Peer Reviewed
Volume 53
Issue 2
Pages 457-470
Keywords Cancer Research; Oncology
Public URL
Publisher URL


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