In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 4397-4397
Abstract:
Background: The anti-epidermal growth factor receptor (EGFR) monoclonal antibodies are the molecular target drugs, dependent on v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations status in metastatic colorectal cancer (mCRC). Anti-EGFR monoclonal antibody based chemotherapy is the standard treatment for mCRC with KRAS wild-type. However, the issue of resistance to this therapy in CRC with KRAS mutations (approximately 50% of CRC) remains unresolved. The aim of this study is to identify microRNAs (miRNAs) that govern the resistance to anti-EGFR monoclonal antibody in CRC with KRAS mutations. Experimental Design: We first established the KRAS mutant cell model using HEK293 and MRC5 cells by introducing KRASG12V plasmid. The miRNA expression profiles were compared between these cells using miRNA microarray analysis. We selected the candidate a miRNA which down-regulates the downstream signal of KRAS using luciferase reporter assays. Assessment of target genes of the candidate a miRNA was performed in vitro. Next, anti-tumor effects by supplement of a miRNA were evaluated in vitro and in vivo. Results: We picked up miRNAs, of which expressions decreased in both HEK293 and MRC5 cells by introduction of KRASG12V plasmid in miRNA array analysis. Among them, administration of mature-miR-X suppressed SRE and AP1 activity in KRAS mutant CRC cell lines such as DLD1G13D, SW480 G12V, and HCT116 G13D using dual luciferase reporter assay. Furthermore, miR-X regulated not only Ras/Raf/MAPK pathway but also suppressed PI3K/Akt pathway in vitro. Administration of mature-miR-X suppressed proliferation and induced apoptosis of the CRC cell lines with KRAS mutations in vitro. Systemic mature-miR-X administration into tail veins of nude mice significantly inhibited the growth of pre-established DLD1G13D xenografts. miR-X level was significantly lower in tumor tissues compared to normal mucosa. Conclusions: miR-X may overcome anti-EGFR therapy resistance in CRC with KRAS mutations by regulating Ras/Raf/MAPK pathway and PI3K/Akt pathway. Our data suggests that miR-X could be suitable for a novel therapy for mCRC patients with KRAS mutations. Citation Format: Masayuki Hiraki, Junichi Nishimura, Mamoru Uemura, Taishi Hata, Ichiro Takemasa, Tsunekazu Mizushima, Hirofumi Yamamoto, Yuichiro Doki, Masaki Mori. Therapeutic microRNA agaisnt KRAS mutant colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4397. doi:10.1158/1538-7445.AM2014-4397
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2014-4397
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2014
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
Permalink