GSTDTAP
DOI10.1126/science.aav4474
Adaptive mutability of colorectal cancers in response to targeted therapies
Russo, Mariangela1,2; Crisafulli, Giovanni1,2; Sogari, Alberto1,2; Reilly, Nicole M.3; Arena, Sabrina1,2; Lamba, Simona1; Bartolini, Alice1; Amodio, Vito1,2; Magri, Alessandro1,2; Novara, Luca1; Sarotto, Ivana1; Nagel, Zachary D.4; Piett, Cortt G.4; Amatu, Alessio5,6; Sartore-Bianchi, Andrea5,6; Siena, Salvatore5,6; Bertotti, Andrea1,2; Trusolino, Livio1,2; Corigliano, Mattia7,8,9; Gherardi, Marco7,8,9; Lagomarsino, Marco Cosentino7,8,9; Di Nicolantonio, Federica1,2; Bardelli, Alberto1,2
2019-12-20
发表期刊SCIENCE
ISSN0036-8075
EISSN1095-9203
出版年2019
卷号366期号:6472页码:1473-+
文章类型Article
语种英语
国家Italy; USA
英文摘要

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.


领域地球科学 ; 气候变化 ; 资源环境
收录类别SCI-E
WOS记录号WOS:000503861000047
WOS关键词STRESS-INDUCED MUTAGENESIS ; PRONE DNA-POLYMERASES ; ANTI-EGFR THERAPY ; ACQUIRED-RESISTANCE ; DRUG-RESISTANCE ; REPAIR ; MUTATIONS ; BLOCKADE ; CELLS ; REPLICATION
WOS类目Multidisciplinary Sciences
WOS研究方向Science & Technology - Other Topics
引用统计
文献类型期刊论文
条目标识符http://119.78.100.173/C666/handle/2XK7JSWQ/226501
专题环境与发展全球科技态势
作者单位1.FPO IRCCS, Candiolo Canc Inst, I-10060 Candiolo, TO, Italy;
2.Univ Torino, Dept Oncol, I-10060 Candiolo, TO, Italy;
3.Fdn Piemontese Ric Canc ONLUS, I-10060 Candiolo, TO, Italy;
4.Harvard TH Chan Sch Publ Hlth, Dept Environm Hlth, JBL Ctr Radiat Sci, Boston, MA 02115 USA;
5.Grande Osped Metropolitano Niguarda, Niguarda Canc Ctr, I-20162 Milan, Italy;
6.Univ Milan, Dept Oncol & Hematooncol, I-20133 Milan, Italy;
7.IFOM FIRC Inst Mol Oncol, I-20139 Milan, Italy;
8.Univ Milan, Dept Phys, I-20133 Milan, Italy;
9.INFN, I-20133 Milan, Italy
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GB/T 7714
Russo, Mariangela,Crisafulli, Giovanni,Sogari, Alberto,et al. Adaptive mutability of colorectal cancers in response to targeted therapies[J]. SCIENCE,2019,366(6472):1473-+.
APA Russo, Mariangela.,Crisafulli, Giovanni.,Sogari, Alberto.,Reilly, Nicole M..,Arena, Sabrina.,...&Bardelli, Alberto.(2019).Adaptive mutability of colorectal cancers in response to targeted therapies.SCIENCE,366(6472),1473-+.
MLA Russo, Mariangela,et al."Adaptive mutability of colorectal cancers in response to targeted therapies".SCIENCE 366.6472(2019):1473-+.
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