Modeling ERBB receptor-regulated G1/S transition to find novel targets for de novo trastuzumab resistance

摘要: In breast cancer, overexpression of the transmembrane tyrosine kinase ERBB2 is an adverse prognostic marker, and occurs in almost 30% patients. For therapeutic intervention, targeted by monoclonal antibody trastuzumab adjuvant settings; however, de novo resistance to this still a serious issue, requiring identification additional targets overcome resistance. study, we have combined computational simulations, experimental testing simulation results, finally reverse engineering protein interaction network define potential strategies for resistant cancer. First, employed Boolean logic model regulatory interactions simulated single multiple loss-of-functions. Then, our results were tested experimentally producing double knockdowns components measuring their effects on G1/S transition during cell cycle progression. Combinatorial targeting EGFR did not affect response cells, which might be due decoupling receptor activation Furthermore, examination c-MYC as well sensitive lines, using specific chemical inhibitor (alone or combination with trastuzumab), demonstrated that both cells responded perturbation. connected ERBB signaling via two major pathways key transcription factors, allows novel treatment Applying new strategy, found that, contrast cancer combinatorial receptors intermediates does cells. Instead, was identified target