Acquired RAS or EGFR mutations and duration of response to EGFR blockade in colorectal cancer
| Autor: | Agostino Ponzetti, Giulia Siravegna, Salvatore Siena, Beatriz Bellosillo, Federica Baldi, Filippo Pietrantonio, Federica Di Nicolantonio, Luca Lazzari, Alberto Bardelli, Benedetta Mussolin, Sabrina Arena, Giovanni Crisafulli, Alice Bartolini, Emanuele Valtorta, Beth O. Van Emburgh, Michela Buscarino, Giorgio Corti, Giovanni Germano, Andrea Sartore-Bianchi, Joan Albanell, Clara Montagut, Joana Vidal |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Colorectal cancer General Physics and Astronomy CLONAL DYNAMICS LUNG-CANCER CELL-LINES RESISTANCE EVOLUTION KRAS HETEROGENEITY ALIGNMENT THERAPY TUMORS medicine.disease_cause Somatic evolution in cancer 0302 clinical medicine Antineoplastic Agents Immunological Epidermal growth factor receptor Aged 80 and over Mutation Multidisciplinary Cetuximab Middle Aged 3. Good health ErbB Receptors Còlon -- Càncer 030220 oncology & carcinogenesis Female Colorectal Neoplasms medicine.drug Adult Science Biology General Biochemistry Genetics and Molecular Biology Article Clonal Evolution 03 medical and health sciences medicine Panitumumab Humans Aged General Chemistry Genes erbB-1 medicine.disease Blockade 030104 developmental biology Genes ras Drug Resistance Neoplasm Immunology Cancer research biology.protein |
| Zdroj: | Nature Communications Nature Communications, Vol 7, Iss 1, Pp 1-9 (2016) |
| ISSN: | 2041-1723 |
| Popis: | Blockade of the epidermal growth factor receptor (EGFR) with the monoclonal antibodies cetuximab or panitumumab is effective in a subset of colorectal cancers (CRCs), but the emergence of resistance limits the efficacy of these therapeutic agents. At relapse, the majority of patients develop RAS mutations, while a subset acquires EGFR extracellular domain (ECD) mutations. Here we find that patients who experience greater and longer responses to EGFR blockade preferentially develop EGFR ECD mutations, while RAS mutations emerge more frequently in patients with smaller tumour shrinkage and shorter progression-free survival. In circulating cell-free tumour DNA of patients treated with anti-EGFR antibodies, RAS mutations emerge earlier than EGFR ECD variants. Subclonal RAS but not EGFR ECD mutations are present in CRC samples obtained before exposure to EGFR blockade. These data indicate that clonal evolution of drug-resistant cells is associated with the clinical outcome of CRC patients treated with anti-EGFR antibodies. Some colorectal cancer patients respond well to treatment with anti-EGFR antibodies, however response is almost invariably followed by acquired resistance. Here, the authors show that patients with shorter responses acquire RAS mutations, while those relapsing later preferentially develop mutations in the extracellular domain of EGFR. |
| Databáze: | OpenAIRE |
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