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

摘要: Attempts at eradicating metastatic cancers with targeted therapies are limited by the emergence of resistant subclones bearing heterogeneous (epi)genetic changes. We used colorectal cancer (CRC) to test hypothesis that interfering an ancestral oncogenic event shared all malignant cells (such as WNT pathway alterations) could override mechanisms acquired drug resistance. Here, we report in CRC-resistant cell populations, phylogenetic analysis uncovers a complex subclonal architecture, indicating parallel evolution multiple independent cellular lineages. Functional and pharmacological modulation signalling induces death CRC preclinical models from patients relapsed during treatment, regardless type or resistance mechanisms. Concomitant blockade MAPK restrains drug-resistant clones. Reliance upon WNT-APC is preserved throughout branched genomic drift associated treatment relapse, thus offering possibility common therapeutic strategy overcome secondary