Abstract LB-455: Reciprocal expression of miR125b and miR192/miR200 families define three clinically relevant sub-types of colorectal cancer with differential sensitivity to EGFR and MEK targeted agents

Abstract

Abstract Global miRNA profiles are particularly informative regarding cell lineage and the differentiation state of tumours. Recent studies also indicate specific miRNAs are upregulated in following drug treatment and in poor prognosis or metastatic disease. The aims of this study were to determine if miRNA profiles could be used to segment a 50 colorectal cell line panel into clinically relevant sub-types and to determine if the miRNA data enhanced prediction of pharmacological response. The global miRNA profile was examined using unsupervised two dimensional hierarchical clustering which revealed a small group of miRNAs which displayed reciprocal expression between the cell line clusters. A subset of 9 miRNAs, miR192 cluster (3 miRs), miR125b (3miRs) cluster and a miR200 negative cluster (3miRs) defined three cell sub-types. These miRs have been associated with intestinal differentiation, poor prognosis/metastasis in CRC and mesenchymal transition respectively. Importantly, the cell sub-types defined by miRNAs directly relate to sub-types defined by iterative clustering of mRNA data in clinical CRC tissue. Analysis of differentially expressed genes between the cell sub-types revealed the expected differences in EMT genes between the miR200 negative cluster and the miR125b and miR192 clusters. Interestingly, the miR192 positive sub-type was discriminated from the miR125b positive cluster by higher expression of several genes specifically associated with intestinal differentiation including CDX1 (71-fold), HNF1a (TCF1) (3-fold), HNF4a (TCF14) (10-fold), HNF4G (5-fold) ISX (12-fold), and IHH (24-fold). Significantly, there were also differences in mRNA expression of genes related to drug sensitivity e.g. ERBB3 (3.6-fold), AREG (3-fold). In contrast, the miR125b subtype had high expression of IRX3 (12-fold) a homeobox gene associated with neural differentiation and increased expression of the oncogene Axl (6-fold). Protein data revealed the miR192 positive sub-type also had higher expression of ERBB2 and B-catenin and lower levels of phosphorylation of AKT substrate, p70S6K and S6 when compared to the miR200 negative and miR125b clusters. The miR192 sub-type also exhibited greater sensitivity to ERB and MEK targeted agents compared to the miR200 and miR125b sub-types. Taken together, the miR data enables segregation by differentiation status, this data enhances prediction of drug activity compared to mutation data alone and is of significance because both miR expression and differentiation status are modulated by prior chemotherapy regimes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-455. doi:1538-7445.AM2012-LB-455