Reliance upon ancestral mutations is maintained in colorectal cancers that heterogeneously evolve during targeted therapies

Attempts at eradicating metastatic cancers with targeted therapies are limited by the emergence of resistant sub-clones bearing heterogeneous (epi)genetic changes. Here we use colorectal cancer to test the hypothesis that interfering with an ancestral oncogenic event shared by all malignant cells (such as WNT pathway alterations) may override heterogeneous molecular mechanisms of acquired drug resistance. Phylogenetic analysis unveils a complex sub-clonal architecture in CRC resistant cell populations, indicating parallel evolution of multiple independent cellular lineages. We demonstrate that functional and pharmacological modulation of WNT signalling induce cell death in CRC preclinical models from patients that relapsed during treatment, regardless of resistance mechanisms. Concomitant blockade of WNT and MAPK signalling restrain evolution of drug-resistant clones. We show that reliance upon the WNT–APC pathway is preserved throughout the branched genomic drift associated with emergence of treatment relapse, thus offering the possibility of a common therapeutic strategy to overcome secondary drug resistance.