MEK inhibitor enhanced the antitumor effect of oxaliplatin and 5‑fluorouracil in MEK1 Q56P‑mutant colorectal cancer cells

Changwen Jing; Huizi Li; Yuanyuan Du; Haixia Cao; Siwen Liu; Zhuo Wang; Rong Ma; Jifeng Feng; Jianzhong Wu

doi:10.3892/mmr.2018.9730

MEK inhibitor enhanced the antitumor effect of oxaliplatin and 5‑fluorouracil in MEK1 Q56P‑mutant colorectal cancer cells

Mol Med Rep. 2019 Feb;19(2):1092-1100. doi: 10.3892/mmr.2018.9730. Epub 2018 Dec 7.

Authors

Changwen Jing^#¹, Huizi Li^#², Yuanyuan Du², Haixia Cao¹, Siwen Liu¹, Zhuo Wang¹, Rong Ma¹, Jifeng Feng³, Jianzhong Wu¹

Affiliations

¹ Clinical Cancer Research Center, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China.
² The Fourth Clinical School of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China.
³ Department of Chemotherapy, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, P.R. China.

^# Contributed equally.

Abstract

Mitogen‑activated protein kinase kinase (MEK) small molecule inhibitors have been investigated in preclinical or clinical trials for the treatment of cancer. In the present study the genetic test results of 120 patients with colorectal cancer (CRC) were screened and the mutation rate of MEK1 was identified to be 1.67%. MEK inhibition by U0126 significantly decreased the growth of SW48 cells that harbored the MEK1 Q56P mutation, although it did not evidently affect the growth of NCI‑H508 cells with MEK1 wild‑type. In addition, U0126 increased the sensitivity of SW48 cells to 5‑fluorouracil (5‑FU) and oxaliplatin by producing more γH2AX foci and decreasing the expression of excision repair cross‑complementation group 1 and thymidylate synthase. The results suggested that MEK inhibitors in combination with oxaliplatin/5‑FU may offer an improved therapeutic effect in patients with MEK‑mutant CRC.

Keywords: colorectal cancer; mitogen-activated protein kinase kinase inhibitor; oxaliplatin; 5-fluorouracil.

MeSH terms

Aged
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Butadienes / pharmacology*
Cell Line, Tumor
Cell Survival / drug effects
Colorectal Neoplasms / genetics
Colorectal Neoplasms / metabolism
Colorectal Neoplasms / pathology
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Drug Synergism
Endonucleases / genetics
Endonucleases / metabolism
Female
Fluorouracil / pharmacology*
Gene Expression Regulation, Neoplastic*
Histones / genetics
Histones / metabolism
Humans
MAP Kinase Kinase 1 / antagonists & inhibitors
MAP Kinase Kinase 1 / genetics*
MAP Kinase Kinase 1 / metabolism
Male
Middle Aged
Mutation
Neoplasm Grading
Neoplasm Metastasis
Neoplasm Staging
Nitriles / pharmacology*
Oxaliplatin / pharmacology*
Signal Transduction
Thymidylate Synthase / genetics
Thymidylate Synthase / metabolism

Substances

Butadienes
DNA-Binding Proteins
H2AX protein, human
Histones
Nitriles
U 0126
Oxaliplatin
Thymidylate Synthase
MAP Kinase Kinase 1
MAP2K1 protein, human
ERCC1 protein, human
Endonucleases
Fluorouracil