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

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.

• Authors: Giulia Siravegna, Benedetta Mussolin, Michela Buscarino, Giorgio Corti, Andrea Cassingena, Giovanni Crisafulli, Agostino Ponzetti, Chiara Cremolini, Alessio Amatu, Calogero Lauricella, Simona Lamba, Sebastijan Hobor, Antonio Avallone, Emanuele Valtorta, Giuseppe Rospo, Enzo Medico, Valentina Motta, Carlotta Antoniotti, Fabiana Tatangelo, Beatriz Bellosillo, Silvio Veronese, Alfredo Budillon, Clara Montagut, Patrizia Racca, Silvia Marsoni, Alfredo Falcone, Ryan B Corcoran, Federica Di Nicolantonio, Fotios Loupakis, Salvatore Siena, Andrea Sartore-Bianchi, Alberto Bardelli
• Journal: Nature medicine (Nat Med) Vol. 21 Issue 7 Pg. 795-801 (Jul 2015) ISSN: 1546-170X [Electronic] United States
• PMID: 26030179 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies
• Antibodies, Neoplasm
• Antineoplastic Agents
• DNA, Neoplasm
• KRAS protein, human
• Proto-Oncogene Proteins
• ErbB Receptors
• Proto-Oncogene Proteins p21(ras)
• ras Proteins

Topics

• Alleles
• Antibodies (pharmacology, therapeutic use)
• Antibodies, Neoplasm (blood)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Clonal Evolution
• Clone Cells
• Colorectal Neoplasms (blood, drug therapy, genetics, pathology)
• DNA, Neoplasm (blood)
• Drug Resistance, Neoplasm (genetics)
• ErbB Receptors (antagonists & inhibitors, genetics, immunology)
• Humans
• Mutation (genetics)
• Proto-Oncogene Proteins (genetics)
• Proto-Oncogene Proteins p21(ras)
• ras Proteins (genetics)