ERK inhibitor: A candidate enhancing therapeutic effects of conventional chemo-radiotherapy in esophageal squamous cell carcinoma

Yanlin Song; Yuan Cheng; Tianxia Lan; Ziyi Bai; Yu Liu; Zhenfei Bi; Aqu Alu; Diou Cheng; Yuquan Wei; Xiawei Wei

doi:10.1016/j.canlet.2022.216012

ERK inhibitor: A candidate enhancing therapeutic effects of conventional chemo-radiotherapy in esophageal squamous cell carcinoma

Cancer Lett. 2023 Feb 1:554:216012. doi: 10.1016/j.canlet.2022.216012. Epub 2022 Dec 5.

Authors

Yanlin Song¹, Yuan Cheng¹, Tianxia Lan¹, Ziyi Bai¹, Yu Liu¹, Zhenfei Bi¹, Aqu Alu¹, Diou Cheng¹, Yuquan Wei¹, Xiawei Wei²

Affiliations

¹ Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
² Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: xiaweiwei@scu.edu.cn.

PMID: 36470544
DOI: 10.1016/j.canlet.2022.216012

Abstract

For patients with esophageal squamous cell carcinoma (ESCC), standard therapeutic methods (cisplatin and radiotherapy) have been found to be ineffective and severely toxic. Targeted therapy emerges as a promising solution for this dilemma. It has been reported that targeted therapies are applied alone or in combination with standard conventional therapies for the treatment of a variety of cancers. To the best of our knowledge, in patients with ESCC, the combinational methods containing standard therapy and ERK-targeted therapy have yet to be explored. To analyze the prognostic role of p-ERK in ESCC patients, the Kaplan-Meier analysis and Cox regression model were used. To assess the effects of ERK-targeted therapy (GDC0994) on ESCC cells, in vitro studies including CCK-8 assay, colony formation assay, and scratch wound healing assay were conducted. In addition, the changes in cell cycle distribution and apoptosis were analyzed by flow cytometry. Besides, to assess the efficacy of different therapies in vivo, the xenograft tumor models were established by subcutaneously inoculating tumor cells into the flank/leg of mice. In patients with ESCC, a strong correlation between the high expression level of p-ERK and the poor prognosis (p < 0.01, Log-Rank test) has been identified. By analyzing the results from CCK-8 and scratch wound healing assays, we demonstrated that the ERK inhibitor repressed the viability and migration of ESCC cells. In addition, following the treatment of GDC0994, the volumes of xenograft tumors significantly decreased (p < 0.001, one-way ANOVA). Furthermore, blocking the mitogen-activated protein kinase (MAPK/ERK) pathway enhanced the therapeutic efficacy of both cisplatin and radiotherapy (p < 0.05). These findings imply the role of p-ERK in the prognosis of ESCC patients and the therapeutic value of ERK inhibitors in ESCC.

Keywords: Cisplatin; ERK inhibitor; Esophageal neoplasma; G2/M arrest; GDC0994; Intrinsic apoptosis; Metastasis; Radiotherapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis
Carcinoma, Squamous Cell* / drug therapy
Carcinoma, Squamous Cell* / genetics
Carcinoma, Squamous Cell* / radiotherapy
Cell Line, Tumor
Cell Proliferation
Chemoradiotherapy / methods
Cisplatin
Esophageal Neoplasms* / drug therapy
Esophageal Neoplasms* / genetics
Esophageal Neoplasms* / radiotherapy
Esophageal Squamous Cell Carcinoma* / drug therapy
Esophageal Squamous Cell Carcinoma* / radiotherapy
Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
Humans
Mice
Protein Kinase Inhibitors / pharmacology

Substances

Cisplatin
Extracellular Signal-Regulated MAP Kinases
Protein Kinase Inhibitors