Acquired resistance to EGFR-targeted therapies in colorectal cancer

作者：Van Emburgh Beth O; Sartore Bianchi Andrea; Di Nicolantonio Federica; Siena Salvatore; Bardelli Alberto^*

来源：Molecular Oncology, 2014, 8(6): 1084-1094.

DOI：10.1016/j.molonc.2014.05.003

• Anti-EGFR therapy
• Cetuximab
• Panitumumab
• Colorectal cancer
• Acquired resistance
• RAS
• MET

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.

• 出版日期2014-9