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Resistance to anti-EGFR therapy in colorectal cancer: from heterogeneity to convergent evolution.
- Source :
-
Cancer discovery [Cancer Discov] 2014 Nov; Vol. 4 (11), pp. 1269-80. Date of Electronic Publication: 2014 Oct 07. - Publication Year :
- 2014
-
Abstract
- Unlabelled: 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.<br />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.<br /> (©2014 American Association for Cancer Research.)
- Subjects :
- Animals
Antibodies, Monoclonal therapeutic use
Antibodies, Monoclonal, Humanized therapeutic use
Cetuximab
Colorectal Neoplasms genetics
Humans
Panitumumab
Antineoplastic Agents therapeutic use
Colorectal Neoplasms drug therapy
Drug Resistance, Neoplasm genetics
ErbB Receptors antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 2159-8290
- Volume :
- 4
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Cancer discovery
- Publication Type :
- Academic Journal
- Accession number :
- 25293556
- Full Text :
- https://doi.org/10.1158/2159-8290.CD-14-0462