EGFR positive feedback loops and βeta Catenin driven miR-17-92 cluster converge to regulate EMT and drug resistance

Abstract

Epidermal growth factor receptor (EGFR)-targeted cancer drug represents a mile- stone in oncology. Nevertheless the responses are invariably limited by the emer- gence of secondary drug-resistance (Misale, Di Nicolantonio et al. 2014). We found that drug-treated ‘‘EGFR-addicted’’ cancer cells engage a positive feedback loop lead- ing to NF-KB/βCatenin axis activation (Lauriola, Enuka et al. 2014), consequently promoting cell survival and limiting overall drug response. Specifically, secondary activation of βCatenin drives the production of an oncogenic cluster of microRNAs 17-92 (Lauriola, Donghwa et al. 2015) implicated in EMT transformation and resist- ance in colon clones. Hence βCatenin and EGFR combination pharmacological inhi- bition overcome the colon spheres growth and enhance tumor regression. These findings suggest that inhibition of EGFR feedback loop along with NF-kB/βCatenin axis may increase the response to a broad spectrum of drugs that target pathways of oncogene addiction.