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.
|Titolo:||Acquired resistance to EGFR-targeted therapies incolorectal cancer|
SIENA, SALVATORE (Penultimo)
|Parole Chiave:||Acquired resistance; Anti-EGFR therapy; Cetuximab; Colorectal cancer; MET; Panitumumab; RAS; Animals; Antineoplastic Agents; Colon; Colorectal Neoplasms; Humans; MAP Kinase Signaling System; Molecular Targeted Therapy; Proto-Oncogene Proteins c-akt; Receptor, Epidermal Growth Factor; Rectum; Signal Transduction; ras Proteins; Drug Resistance, Neoplasm; Cancer Research; Genetics; Molecular Medicine; Medicine (all)|
|Settore Scientifico Disciplinare:||Settore MED/06 - Oncologia Medica|
|Data di pubblicazione:||set-2014|
|Digital Object Identifier (DOI):||10.1016/j.molonc.2014.05.003|
|Appare nelle tipologie:||01 - Articolo su periodico|