Adaptive mutability of colorectal cancers in response to targeted therapies

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...

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Vydáno v:Science (American Association for the Advancement of Science) Ročník 366; číslo 6472; s. 1473
Hlavní autoři: Russo, Mariangela, Crisafulli, Giovanni, Sogari, Alberto, Reilly, Nicole M, Arena, Sabrina, Lamba, Simona, Bartolini, Alice, Amodio, Vito, Magrì, Alessandro, Novara, Luca, Sarotto, Ivana, Nagel, Zachary D, Piett, Cortt G, Amatu, Alessio, Sartore-Bianchi, Andrea, Siena, Salvatore, Bertotti, Andrea, Trusolino, Livio, Corigliano, Mattia, Gherardi, Marco, Lagomarsino, Marco Cosentino, Di Nicolantonio, Federica, Bardelli, Alberto
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 20.12.2019
Témata:
Adaptation, Biological - genetics
Colorectal Neoplasms - drug therapy
Colorectal Neoplasms - genetics
DNA Mismatch Repair - genetics
Down-Regulation
Drug Resistance, Neoplasm - genetics
ErbB Receptors - antagonists & inhibitors
Humans
Molecular Targeted Therapy
Mutagenesis
Proto-Oncogene Proteins B-raf - antagonists & inhibitors
Selection, Genetic
ISSN:1095-9203, 1095-9203
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Shrnutí: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.
Bibliografie:ObjectType-Article-1
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ISSN:1095-9203
1095-9203
DOI:10.1126/science.aav4474