HKI-272 contributes to gemcitabine-mediated anti-proliferative and anti-metastatic effects through EGFR suppression in gallbladder cancer

Xuli Yang; Tao Chen; Jie Hu; Jian Wang; Dong Yang

doi:10.1016/j.omto.2022.10.004

HKI-272 contributes to gemcitabine-mediated anti-proliferative and anti-metastatic effects through EGFR suppression in gallbladder cancer

Mol Ther Oncolytics. 2022 Oct 8:27:126-140. doi: 10.1016/j.omto.2022.10.004. eCollection 2022 Dec 15.

Authors

Xuli Yang¹, Tao Chen², Jie Hu³, Jian Wang², Dong Yang⁴

Affiliations

¹ Department of Anesthesiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, China.
² Department of Biliary-Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
³ Department of Anesthesiology, The Second Affiliated Hospital of University of South China, Hengyang, Hunan 421001, China.
⁴ Department of Gastroenterology and Pancreatic Surgery, The Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, Jiangsu 211100, China.

Abstract

Gallbladder cancer (GBC) is a rare malignancy of the biliary system and characterized by early metastasis and poor prognosis. To date, no efficient treatment is available for GBC patients. Based on the data from cBioPortal, TIMER, and GDSC, we performed an unbiased screening with 25 candidate compounds that predominantly target ErbB family and identified HKI-272, a highly selective EGFR/ErbB2 inhibitor, displayed decreased IC₅₀ values in three GBC cell lines. HKI-272 not only promoted gemcitabine-mediated anti-proliferative and pro-apoptotic effects and induced cell cycle arrest in GBC, but also enhanced gemcitabine-induced suppressive effects of GBC cell migration and invasion by inhibiting pathways downstream of EGFR. Furthermore, HKI-272, together with gemcitabine, effectively suppressed tumor growth and metastases in mouse models. Immunostaining and HE staining data from both primary tumor and lung metastasis indicated that the anti-proliferative and anti-metastatic effects were mediated through EGFR suppression. Moreover, the expression of EGFR, measured by both immunostaining and HE staining, was correlated with a poor prognosis in GBC. In addition, EGFR in tumor tissues are independent indicators for overall survival in GBC patients. Taken together, our findings suggest that HKI-272 could be a potential therapeutic agent and EGFR might serve as a potential biomarker for patients with GBC.

Keywords: EGFR; HKI-272; gallbladder cancer; gemcitabine; small molecule inhibitor.