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

Mariangela Russo, Simona Lamba, Annalisa Lorenzato, Alberto Sogari, Giorgio Corti, Giuseppe Rospo, Benedetta Mussolin, Monica Montone, Luca Lazzari, Sabrina Arena, Daniele Oddo, Michael Linnebacher, Andrea Sartore-Bianchi, Filippo Pietrantonio, Salvatore Siena, Federica Di Nicolantonio, Alberto Bardelli

Research output: Contribution to journalArticle

Abstract

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 the hypothesis that interfering with an ancestral oncogenic event shared by all the malignant cells (such as WNT pathway alterations) could override heterogeneous mechanisms of acquired drug resistance. Here, we report that in CRC-resistant cell populations, phylogenetic analysis uncovers a complex subclonal architecture, indicating parallel evolution of multiple independent cellular lineages. Functional and pharmacological modulation of WNT signalling induces cell death in CRC preclinical models from patients that relapsed during the treatment, regardless of the drug type or resistance mechanisms. Concomitant blockade of WNT and MAPK signalling restrains the emergence of drug-resistant clones. 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.

Original languageEnglish
Article number2287
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - Dec 1 2018

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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