Portal de Periódicos da CAPES

Vertical suppression of the EGFR pathway prevents onset of resistance in colorectal cancers

2015; Nature Portfolio; Volume: 6; Issue: 1 Linguagem: Inglês

10.1038/ncomms9305

2041-1723

Sandra Misale, Ivana Božić, Jingshan Tong, Ashley Peraza-Penton, Alice Lallo, Federica Baldi, Kevin Lin, Mauro Truini, Livio Trusolino, Andrea Bertotti, Federica Di Nicolantonio, Martin A. Nowak, Lin Zhang, Kris C. Wood, Alberto Bardelli,

Cancer Genomics and Diagnostics

Abstract Molecular targeted drugs are clinically effective anti-cancer therapies. However, tumours treated with single agents usually develop resistance. Here we use colorectal cancer (CRC) as a model to study how the acquisition of resistance to EGFR-targeted therapies can be restrained. Pathway-oriented genetic screens reveal that CRC cells escape from EGFR blockade by downstream activation of RAS-MEK signalling. Following treatment of CRC cells with anti-EGFR, anti-MEK or the combination of the two drugs, we find that EGFR blockade alone triggers acquired resistance in weeks, while combinatorial treatment does not induce resistance. In patient-derived xenografts, EGFR-MEK combination prevents the development of resistance. We employ mathematical modelling to provide a quantitative understanding of the dynamics of response and resistance to these single and combination therapies. Mechanistically, we find that the EGFR-MEK Combo blockade triggers Bcl-2 and Mcl-1 downregulation and initiates apoptosis. These results provide the rationale for clinical trials aimed at preventing rather than intercepting resistance.