Massively parallel genetic resistance screens

Here we describe the use of multiple forward genetic screens executed in parallel to identify those genes, and their cognate pathways, that when overexpressed, silenced or mutated confer resistance in BRAF mutant colon cancer to a BRAF/MEK/EGFR inhibitor combination. We demonstrate that this resistance landscape is finite, relatively constrained to a small number of pathways and that it is possible to exploit the evolutionary dynamics that underpins the clonal expansion of drug resistant cells therapeutically.