Abstract P6-04-25: Genomic Deregulation and Therapeutic Role of Nemo-like Kinase in Luminal B Breast Cancer

Abstract

Abstract Luminal B breast tumors are notoriously known as high grade breast cancer prone to Tamoxifen resistance and early recurrence. Chromosomal abnormalities are a crucial class of drug targets in cancer which can be classified into numerical and structural rearrangements. Gene amplification is the result of numerical rearrangement that generates multiple copies of an otherwise normal human gene, such as Her2 amplification observed in breast cancer. Gene fusion is the result of structural rearrangement that fuses together pieces of two different genes, such as BCR-ABL gene fusion identified in leukemia. Due to their critical role in causing human cancers and their presence exclusively in the tumor tissues, gene amplifications and fusions provide highly specific drug targets with only minimal side effects. In order to identify these chromosome aberrations that can serve as new therapeutic targets in breast cancer, we developed a novel bioinformatics analysis called “copy number signature analysis”. This is based on the observation that driving gene fusions and their original (wild-type) genes are often amplified in fusion-positive tumors, or tumors without the fusions respectively. This suggests that gene fusions and amplifications may synergize to activate important oncogenes; if directly druggable, these aberrations will provide substantial opportunities for new therapies. Applying this analysis to the newly emerged genomic data from the Cancer Genome Atlas (TCGA) project nominated Nemo-like kinase (NLK) as a lead therapeutic target for invasive breast cancer. NLK encodes a serine-threonine mitogen activated protein kinase that plays a pivotal role in transforming growth factor beta pathway and embryo development. Genomic amplifications and rearrangements at NLK locus happen in 7%–9% of breast tumors, which may lead to deregulated serine-threonine kinase activity. Of note, these aberrations preferentially present in luminal B or Her2 positive breast tumors, suggesting their association with these high grade tumors. Most interestingly, transient inhibition of NLK through small RNA interference in multiple breast cancer cell lines harboring NLK deregulations, we observed potent inhibition of cell growth and capability of forming tumor-like colonies, as well as increased sensitivity to Tamoxifen treatment. These data suggest that NLK might be deregulated by genetic events which may promote growth-factor signaling and Tamoxifen resistant phenotype. Molecular assays detecting NLK chromosomal aberrations may serve as a predictive biomarker for endocrine resistance in breast cancer as well as selection of patients for appropriate treatment. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-25.