Journal
MOLECULAR ONCOLOGY
Volume 8, Issue 6, Pages 1084-1094Publisher
WILEY
DOI: 10.1016/j.molonc.2014.05.003
Keywords
Anti-EGFR therapy; Cetuximab; Panitumumab; Colorectal cancer; Acquired resistance; RAS; MET
Categories
Funding
- European Community's Seventh Framework Programme [259015COLTHERES]
- AIRC IG grant [12812]
- AIRC MFAG [11349]
- Farmacogenomica -5 per mille MIUR - Fondazione Piemontese per la Ricerca sul Cancro - ONLUS
- AIRC Special Program Molecular Clinical Oncology 5 per mille [9970]
- FPRC 5 per mille Minister della Salute
- Ministero dell'Istruzione, dell'Universita e della Ricerca, progetto PRIN
- Progetti di Ateneo, Universita di Torino [ORTO11RKTW]
- Oncologia Ca' Granda ONLUS (OCGO) Fondazione
- Grant Terapia Molecolare dei Tumori from Oncologia Ca' Granda Onlus (OCGO) Fondazione
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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. (C) 2014 Published by Elsevier B.V. on behalf of Federation of European Biochemical Societies.
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