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.

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

SIRAVEGNA, GIULIA;Crisafulli, Giovanni;PONZETTI, AGOSTINO;LAMBA, SIMONA ELENA;Rospo, Giuseppe;MEDICO, Enzo;DI NICOLANTONIO, Federica;BARDELLI, Alberto
Last
2015-01-01

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.
2015
Inglese
Esperti anonimi
21
7
795
801
7
http://www.nature.com/nm/journal/v21/n7/abs/nm.3870.html
L'articolo è stato messo in evidenza da un Editoriale apparso sulla stessa rivista. Meador CB, Lovly CM. Liquid biopsies reveal the dynamic nature of resistance mechanisms in solid tumors. Nat Med. 2015 Jul;21(7):663-5. doi: 10.1038/nm.3899. Recensito in Turajlic S, Swanton C; Gastrointestinal cancer: Tracking tumour evolution through liquid biopsy; Nat Rev Clin Oncol. 2015 Oct;12(10):565-6. doi: 10.1038/nrclinonc.2015.153
DROPLET DIGITAL PCR; FREE TUMOR DNA; KRAS MUTATIONS; ACQUIRED-RESISTANCE; SENSITIVE DETECTION; DRUG-RESISTANCE; NUCLEIC-ACIDS; HETEROGENEITY; MELANOMA; THERAPY
REGNO UNITO DI GRAN BRETAGNA
SPAGNA
STATI UNITI D'AMERICA
   FP7
1 – prodotto con file in versione Open Access (allegherò il file al passo 6 - Carica)
262
32
Siravegna, Giulia; Mussolin, Benedetta; Buscarino, Michela; Corti, Giorgio; Cassingena, Andrea; Crisafulli, Giovanni; Ponzetti, Agostino; Cremolini, C...espandi
info:eu-repo/semantics/article
partially_open
03-CONTRIBUTO IN RIVISTA::03A-Articolo su Rivista
File in questo prodotto:
File Dimensione Formato  
2015-Clonal evolution.pdf

Accesso riservato

Tipo di file: PDF EDITORIALE
Dimensione 672.66 kB
Formato Adobe PDF
672.66 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
2015-Clonal evolution_post print.pdf

Open Access dal 02/03/2016

Tipo di file: POSTPRINT (VERSIONE FINALE DELL’AUTORE)
Dimensione 840.4 kB
Formato Adobe PDF
840.4 kB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1530472
Citazioni
  • ???jsp.display-item.citation.pmc??? 379
  • Scopus 715
  • ???jsp.display-item.citation.isi??? 686
social impact