Down-regulation of mitogen-inducible gene 6, a negative regulator of EGFR, enhances resistance to MEK inhibition in KRAS mutant cancer cells

Young-Kwang Yoon; Hwang-Phill Kim; Sang-Hyun Song; Sae-Won Han; Do Youn Oh; Seock-Ah Im; Yung-Jue Bang; Tae-You Kim

doi:10.1016/j.canlet.2011.10.023

Down-regulation of mitogen-inducible gene 6, a negative regulator of EGFR, enhances resistance to MEK inhibition in KRAS mutant cancer cells

Cancer Lett. 2012 Mar;316(1):77-84. doi: 10.1016/j.canlet.2011.10.023. Epub 2011 Oct 23.

Authors

Young-Kwang Yoon¹, Hwang-Phill Kim, Sang-Hyun Song, Sae-Won Han, Do Youn Oh, Seock-Ah Im, Yung-Jue Bang, Tae-You Kim

Affiliation

¹ Cancer Research Institute, Seoul National University College of Medicine, South Korea.

PMID: 22082529
DOI: 10.1016/j.canlet.2011.10.023

Abstract

Previously, we found that KRAS mutant cancer cells showed variable response to AZD6244, a MEK inhibitor through differential activation of EGFR/AKT. To investigate its mechanism, we performed cDNA microarray using four KRAS mutant cancer cells. We found that treatment with AZD6244 reduced the expression of mitogen-inducible gene 6 (MIG6), a negative feedback regulator for EGFR, in AZD6244-resistant cells, while activity of EGFR and AKT was increased in these cells. Reconstitution or knockdown of MIG6 expression affected cancer cell responses to AZD6244. Treatment with a combination of EGFR inhibitor and AZD6244 inhibited cell proliferation synergistically without activation of AKT in AZD6244-resistant cells. Our study provides a mechanism of differential response to MEK inhibition in KRAS mutant cancer.

Publication types

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

MeSH terms

Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
Adaptor Proteins, Signal Transducing / genetics*
Adaptor Proteins, Signal Transducing / metabolism
Benzimidazoles / pharmacology
Cell Growth Processes / genetics
Cell Line, Tumor
Down-Regulation
Drug Resistance, Neoplasm
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / genetics*
ErbB Receptors / metabolism
Gene Knockdown Techniques / methods
HCT116 Cells
Humans
MAP Kinase Kinase Kinases / antagonists & inhibitors*
MAP Kinase Kinase Kinases / metabolism
Mutation
Oligonucleotide Array Sequence Analysis / methods
Proto-Oncogene Proteins / genetics*
Proto-Oncogene Proteins c-akt / metabolism
Proto-Oncogene Proteins p21(ras)
Tumor Suppressor Proteins / antagonists & inhibitors*
Tumor Suppressor Proteins / genetics*
Tumor Suppressor Proteins / metabolism
ras Proteins / genetics*

Substances

AZD 6244
Adaptor Proteins, Signal Transducing
Benzimidazoles
ERRFI1 protein, human
KRAS protein, human
Proto-Oncogene Proteins
Tumor Suppressor Proteins
EGFR protein, human
ErbB Receptors
Proto-Oncogene Proteins c-akt
MAP Kinase Kinase Kinases
Proto-Oncogene Proteins p21(ras)
ras Proteins