Abstract
The rapid onset of resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) limits its clinical utility in colorectal cancer (CRC) patients, and pan-erb-b2 receptor tyrosine kinase (ErbB) treatment strategy may be the alternative solution. The aim of this study was to develop a possible microRNA multi-ErbB treatment strategy to overcome EGFR-TKI resistance. We detect the receptor tyrosine kinase activity in gefitinib-resistant colorectal cancer cells, ErbB3/EGFR is significantly activated and provides a potential multi-ErbB treatment target. MiR-323a-3p, a tumor suppressor, could target both ErbB3 and EGFR directly. Apoptosis is the miR-323a-3p inducing main biological process by functional enrichment analysis, and The EGFR and ErbB signaling are the miR-323a-3p inducing main pathway by KEGG analysis. MiR-323a-3p promotes CRC cells apoptosis by targeting ErbB3-phosphoinositide 3-kinases (PI3K)/PKB protein kinase (Akt)/glycogen synthase kinase 3 beta (GSK3β)/EGFR-extracellular regulated MAP kinase (Erk1/2) signaling directly. And miR-323a-3p, as a multi-ErbBs inhibitor, increase gefitinib sensitivity of the primary cell culture from combination miR-323a-3p and gefitinib treated subcutaneous tumors. MiR-323a-3p reverses ErbB3/EGFR signaling activation in gefitinib-resistant CRC cell lines and blocks acquired gefitinib resistance.