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Cited by 1,082

The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index.

Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients

Open access
Siravegna, Giulia, Mussolin, Benedetta, Buscarino, Michela, Corti, Giorgio, Cassingena, Andrea, Crisafulli, Giovanni, Ponzetti, Agostino, Cremolini, Chiara, Amatu, Alessio, Lauricella, Calogero, Lamba, Simona, Hobor, Sebastijan, Avallone, Antonio, Valtorta, Emanuele, Rospo, Giuseppe, Medico, Enzo, Motta, Valentina, Antoniotti, Carlotta, Tatangelo, Fabiana, Bellosillo, Beatriz, Veronese, Silvio, Budillon, Alfredo, Montagut, Clara, Racca, Patrizia, Marsoni, Silvia, Falcone, Alfredo, Corcoran, Ryan B, Di Nicolantonio, Federica, Loupakis, Fotios, Siena, Salvatore, Sartore-Bianchi, Andrea, Bardelli, Alberto·2015·Nature Medicine
DOI 10.1038/nm.3870
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Abstract

Colorectal cancers (CRCs) evolve by a reiterative process of genetic diversification and clonal evolution. The molecular profile of CRC is routinely assessed in surgical or bioptic samples. Genotyping of CRC tissue has inherent limitations; a tissue sample represents a single snapshot in time, and it is subjected to spatial selection bias owing to tumor heterogeneity. Repeated tissue samples are difficult to obtain and cannot be used for dynamic monitoring of disease progression and response to therapy. We exploited circulating tumor DNA (ctDNA) to genotype colorectal tumors and track clonal evolution during treatment with the epidermal growth factor receptor (EGFR)-specific antibodies cetuximab or panitumumab. We identified alterations in ctDNA of patients with primary or acquired resistance to EGFR blockade in the following genes: KRAS, NRAS, MET, ERBB2, FLT3, EGFR and MAP2K1. Mutated KRAS clones, which emerge in blood during EGFR blockade, decline upon withdrawal of EGFR-specific antibodies, indicating that clonal evolution continues beyond clinical progression. Pharmacogenomic analysis of CRC cells that had acquired resistance to cetuximab reveals that upon antibody withdrawal KRAS clones decay, whereas the population regains drug sensitivity. ctDNA profiles of individuals who benefit from multiple challenges with anti-EGFR antibodies exhibit pulsatile levels of mutant KRAS. These results indicate that the CRC genome adapts dynamically to intermittent drug schedules and provide a molecular explanation for the efficacy of rechallenge therapies based on EGFR blockade.

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Authors
Siravegna, G., Mussolin, B., Buscarino, M., Corti, G., Cassingena, A., Crisafulli, G., Ponzetti, A., Cremolini, C., Amatu, A., Lauricella, C., Lamba, S., Hobor, S., Avallone, A., Valtorta, E., Rospo, G., Medico, E., Motta, V., Antoniotti, C., Tatangelo, F., Bellosillo, B., Veronese, S., Budillon, A., Montagut, C., Racca, P., Marsoni, S., Falcone, A., Corcoran, R. B., Di Nicolantonio, F., Loupakis, F., Siena, S., Sartore-Bianchi, A., & Bardelli, A.
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2015-06-01
Volume
21
Issue
7
Pages
795-801
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm.3870
OpenAlex
W1914351667
Cited by
1,082
References
48
FWCI
36.80
Type
journal article
Language
en
Open access
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