Adaptive mutability of colorectal cancers in response to targeted therapies

Mariangela Russo, Giovanni Crisafulli, Alberto Sogari, Nicole M Reilly, Sabrina Arena, Simona Lamba, Alice Bartolini, Vito Amodio, Alessandro Magrì, Luca Novara, Ivana Sarotto, Zachary D Nagel, Cortt G Piett, Alessio Amatu, Andrea Sartore-Bianchi, Salvatore Siena, Andrea Bertotti, Livio Trusolino, Mattia Corigliano, Marco GherardiMarco Cosentino Lagomarsino, Federica Di Nicolantonio, Alberto Bardelli

Research output: Contribution to journalArticle

Abstract

The emergence of drug resistance limits the efficacy of targeted therapies in human tumors. The prevalent view is that resistance is a fait accompli: when treatment is initiated, cancers already contain drug-resistant mutant cells. Bacteria exposed to antibiotics transiently increase their mutation rates (adaptive mutability), thus improving the likelihood of survival. We investigated whether human colorectal cancer (CRC) cells likewise exploit adaptive mutability to evade therapeutic pressure. We found that epidermal growth factor receptor (EGFR)/BRAF inhibition down-regulates mismatch repair (MMR) and homologous recombination DNA-repair genes and concomitantly up-regulates error-prone polymerases in drug-tolerant (persister) cells. MMR proteins were also down-regulated in patient-derived xenografts and tumor specimens during therapy. EGFR/BRAF inhibition induced DNA damage, increased mutability, and triggered microsatellite instability. Thus, like unicellular organisms, tumor cells evade therapeutic pressures by enhancing mutability.

Original languageEnglish
Pages (from-to)1473-1480
Number of pages8
JournalScience
Volume366
Issue number6472
DOIs
Publication statusPublished - Dec 20 2019

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  • Cite this

    Russo, M., Crisafulli, G., Sogari, A., Reilly, N. M., Arena, S., Lamba, S., Bartolini, A., Amodio, V., Magrì, A., Novara, L., Sarotto, I., Nagel, Z. D., Piett, C. G., Amatu, A., Sartore-Bianchi, A., Siena, S., Bertotti, A., Trusolino, L., Corigliano, M., ... Bardelli, A. (2019). Adaptive mutability of colorectal cancers in response to targeted therapies. Science, 366(6472), 1473-1480. https://doi.org/10.1126/science.aav4474