title: Down-regulation of mitogen-inducible gene 6, a negative regulator of EGFR, enhances resistance to MEK inhibition in KRAS mutant cancer cells.
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.
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, South Korea.
authors.forename: Young-Kwang
authors.initials: YK
authors.lastname: Yoon
authors.forename: Hwang-Phill
authors.initials: HP
authors.lastname: Kim
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Song
authors.forename: Sae-Won
authors.initials: SW
authors.lastname: Han
authors.forename: Do Youn
authors.initials: DY
authors.lastname: Oh
authors.forename: Seock-Ah
authors.initials: SA
authors.lastname: Im
authors.forename: Yung-Jue
authors.initials: YJ
authors.lastname: Bang
authors.forename: Tae-You
authors.initials: TY
authors.lastname: Kim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D001562:Benzimidazoles / Q000494:pharmacology; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D055785:Gene Knockdown Techniques / Q000379:methods; D045325:HCT116 Cells; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics*
chemical_list: C517975:AZD 6244; D048868:Adaptor Proteins, Signal Transducing; D001562:Benzimidazoles; C484017:ERRFI1 protein, human; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D020930:MAP Kinase Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins