期刊
CANCER DISCOVERY
卷 4, 期 11, 页码 1269-1280出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-14-0462
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资金
- European Community [259015 COLTHERES]
- Associazione Italiana per la Ricerca sul Cancro (AIRC) IG [12812]
- AIRC MFAG [11349]
- Farmacogenomica-5 per mille 2009 MIUR-Fondazione Piemontese per la Ricerca sul Cancro ONTUS
- AIRC [9970]
- Ministero dell'Istruzione, e della Ricerca, progetto PRIN
- Universita di Torino [ORTO11RKTW]
- Oncologia Ca' Granda (OCGO) Fondazione
- grant Identification and monitoring of gene mutations in peripheral blood and urine as a diagnostic tool for patients with solid tumors from Regione Lombardia
- Ministero Salute
- grant Liquid Biopsy-5 per mille Ministero della Salute-Fondazione Piemontese per la Ricerca sul Cancro ONLUS
- grant Precision Oncology-5 per mille Ministero della Salute Fondazione Piemontese per la Ricerca sul Cancro ONLUS
The EGFR-targeted antibodies cetuximab and panitumumab are used to treat metastatic colorectal cancers. Mutations in KRAS, NRAS, and BRAF and amplification of ERBB2 and MET drive primary (de novo) resistance to anti-EGFR treatment. Recently, the emergence of alterations in the same genes was detected in patients who responded to EGFR blockade and then relapsed. These results illuminate a striking overlap between genes that, when mutated, drive primary and secondary resistance to anti-EGFR antibodies. Remarkably, although the mechanisms of resistance are genetically heterogeneous, they biochemically converge on key signaling pathways. This knowledge is being translated in the rational design of additional lines of therapy. Significance: Anti-EGFR-targeted therapies are used for the treatment of metastatic colorectal cancer. Molecular heterogeneity impairs their efficacy by fuelling de novo and acquired resistance. In this review, we highlight how genetically distinct resistance mechanisms biochemically converge on a limited number of signaling pathways that can be therapeutically intercepted. (C) 2014 AACR.
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