Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Apr 21, 2019; 25(15): 1840-1853
Published online Apr 21, 2019. doi: 10.3748/wjg.v25.i15.1840
Predictive and prognostic implications of 4E-BP1, Beclin-1, and LC3 for cetuximab treatment combined with chemotherapy in advanced colorectal cancer with wild-type KRAS: Analysis from real-world data
Gui-Fang Guo, Yi-Xing Wang, Yi-Jun Zhang, Xiu-Xing Chen, Jia-Bin Lu, Hao-Hua Wang, Chang Jiang, Hui-Quan Qiu, Liang-Ping Xia
Gui-Fang Guo, Yi-Xing Wang, Xiu-Xing Chen, Hao-Hua Wang, Chang Jiang, Hui-Quan Qiu, Liang-Ping Xia, VIP Department, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong Province, China
Gui-Fang Guo, Yi-Xing Wang, Yi-Jun Zhang, Xiu-Xing Chen, Jia-Bin Lu, Hao-Hua Wang, Chang Jiang, Hui-Quan Qiu, Liang-Ping Xia, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong Province, China
Gui-Fang Guo, Yi-Xing Wang, Yi-Jun Zhang, Xiu-Xing Chen, Jia-Bin Lu, Hao-Hua Wang, Chang Jiang, Hui-Quan Qiu, Liang-Ping Xia, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, Guangdong Province, China
Yi-Jun Zhang, Jia-Bin Lu, Pathology Department, Sun Yat-sen University Cancer Center, Guangzhou 510060, Guangdong Province, China
Author contributions: Guo GF designed the research; Guo GF and Wang YX analyzed the data and wrote the paper; Chen XX and Wang HH performed the experiments; Zhang YJ and Lu JB contributed new reagents and analytic tools; Jiang C and Qiu HQ collected the data; Xia LP amended the paper; all of the authors have read and approved the final manuscript.
Institutional review board statement: This study was approved by the Ethics Committee of the Sun Yat-sen University Cancer Center, Guangdong, China. All patients involved in this study gave their informed consent for participation in the study.
Conflict-of-interest statement: The authors have no conflict of interest relevant to this study.
Data sharing statement: The manuscript has no additional data available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Gui-Fang Guo, MD, PhD, Professor, VIP Department, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510060, Guangdong Province, China. guogf@sysucc.org.cn
Telephone: +86-20-87342708 Fax: +86-20-87342708
Received: January 24, 2019
Peer-review started: January 24, 2019
First decision: February 26, 2019
Revised: March 20, 2019
Accepted: March 24, 2019
Article in press: March 25 2019
Published online: April 21, 2019
Processing time: 84 Days and 16.7 Hours
ARTICLE HIGHLIGHTS
Research background

Great effects have been made in exploring the treatment of colorectal cancer (CRC), but the effectiveness is still limited due to the limited drug selection. Cetuximab, a monoclonal antibody targeting epidermal growth factor receptor (EGFR), significantly increased OS (overall survival) of advanced CRC patients (ACRC). But the response rate (RR) is only 40%-60% for patients with wild-type KRAS. Autophagy, showing a key role in the cancer progression and induced by EGFR siRNA, may allow to develop effective strategies for improving cetuximab effect in CRC, while there have been few studies regarding the predictive role of autophagy in ACRC patients with wild-type KRAS.

Research motivation

Autophagy-related factors were investigated in ACRC with wild-type KRAS to find new biomarkers for cetuximab efficacy, which may offer the potential for developing novel therapeutic strategies for these patients.

Research objectives

The role of Beclin1, microtubule-associated protein 1A/B-light chain 3 (LC3), and 4E-binding protein 1 (4E-BP1), the key factors in autophagy, in predicting the efficacy of cetuximab in ACRC with wild-type KRAS was explored. It was found that Beclin1 and 4E-BP1 were independent prognostic factors for overall survival (OS). In the future research, elucidating the molecular mechanism of association of these factors with cetuximab may help us find more new biomarkers and make cetuximab treatment more accurate.

Research methods

We detected the expression of autophagy-related proteins 4E-BP1, Beclin-1, and LC3 in CRC samples and adjacent non-tumor tissues by immunohistochemistry. And the three proteins were examined by Western blot in CRC cells. The effect of autophagy on cetuximab-treated cancer cells was confirmed by MTT assay. The associations of Beclin1, LC3, and 4E-BP1 expression in tumor tissue with the efficacy of cetuximab-based therapy were analyzed.

Research results

Autophagosome formation was observed in colon cancer cells, with LC3 and 4E-BP1 upregulated, and autophagy increased the efficacy of cetuximab. Beclin1 expression was significantly correlated with LC3 and 4E-BP1 expression in ACRC tissues. LC3 was significantly overexpressed in tumor tissues compared to normal tissues. In patients with wild-type KRAS, the expression levels of Beclin1 and 4E-BP1 were independent prognostic factors for OS. The molecular mechanism of association of these factors with cetuximab effect and their weight coefficients in prognostic models need further study.

Research conclusions

LC3 is overexpressed in tumor tissues, and Beclin1 and 4E-BP1 are significant predictors of OS in wild-type KRAS ACRC treated with cetuximab. Autophagy has a role in improving the effects of cetuximab on colon cancer cell.

Research perspectives

Autophagy might play a new role to predict the effects of cetuximab in ACRC with wild-type KRAS in the future, and inducing or blocking autophagy may be a new way to improve cetuximab treating ACRC.