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EnglishCetuximab and panitumumab are anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies used as therapies for metastatic colorectal cancer patients. Intrinsic mechanisms of resistance, such as RAS mutations, can prevent patients from having a response with clinical benefit. The clinical efficacy of EGFR targeted antibodies is limited by the development of acquired (secondary) resistance, which typically occurs within 3-12 months from the start of therapy. Preclinical models and analyses of clinical samples have uncovered some of the alterations that confer a selective advantage to tumor cells when under the pressure of anti-EGFR therapy. Molecular profiling of clinical specimens confirmed that genetic alterations of genes in the EGFR-RAS-RAF-MEK signaling pathway and of receptor tyrosine kinases are mechanisms of acquired resistance to anti-EGFR antibodies. The escape from anti-EGFR blockade appears to converge on the (re)activation of MEK-ERK or AKT as revealed in preclinical studies. Circulating tumor DNA and patient derived xenografts have proven useful tools to monitor patients for resistance to anti-EGFR therapy and test combination therapies to overcome or reverse resistance.
| Titolo: | Acquired resistance to EGFR-targeted therapies in colorectal cancer. |
| Autori Riconosciuti: | |
| Autori: | Van Emburgh BO;Sartore-Bianchi A;Di Nicolantonio F;Siena S;Bardelli A |
| Data di pubblicazione: | 2014 |
| Abstract: | Cetuximab and panitumumab are anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies used as therapies for metastatic colorectal cancer patients. Intrinsic mechanisms of resistance, such as RAS mutations, can prevent patients from having a response with clinical benefit. The clinical efficacy of EGFR targeted antibodies is limited by the development of acquired (secondary) resistance, which typically occurs within 3-12 months from the start of therapy. Preclinical models and analyses of clinical samples have uncovered some of the alterations that confer a selective advantage to tumor cells when under the pressure of anti-EGFR therapy. Molecular profiling of clinical specimens confirmed that genetic alterations of genes in the EGFR-RAS-RAF-MEK signaling pathway and of receptor tyrosine kinases are mechanisms of acquired resistance to anti-EGFR antibodies. The escape from anti-EGFR blockade appears to converge on the (re)activation of MEK-ERK or AKT as revealed in preclinical studies. Circulating tumor DNA and patient derived xenografts have proven useful tools to monitor patients for resistance to anti-EGFR therapy and test combination therapies to overcome or reverse resistance. |
| Volume: | 8 |
| Fascicolo: | 6 |
| Pagina iniziale: | 1084 |
| Pagina finale: | 1094 |
| Digital Object Identifier (DOI): | 10.1016/j.molonc.2014.05.003 |
| URL: | http://www.moloncol.org/article/S1574-7891(14)00096-9/fulltext |
| Parole Chiave: | colorectal cancer; cetuximab; panitumumab; EGFR; Drug Resistance |
| Rivista: | MOLECULAR ONCOLOGY |
| Appare nelle tipologie: | 03B-Review in Rivista / Rassegna della Lett. in Riv. / Nota Critica |
File in questo prodotto:
| File | Descrizione | Tipologia | Licenza | |
|---|---|---|---|---|
| VanEmburgh_2014_review_1-s2.0-S1574789114000969-main.pdf | PDF EDITORIALE | Accesso riservato | Utenti riconosciuti Richiedi una copia | |
| POST_2014-Van Emburgh et al_Acquired_4aperto.pdf | POSTPRINT (VERSIONE FINALE DELL’AUTORE) | Accesso aperto | Open Access Visualizza/Apri |
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