Acquired resistance to EGFR‐targeted therapies in colorectal cancer

Molecular Oncology - Tập 8 - Trang 1084-1094 - 2014
Beth O. Van Emburgh1,2, Andrea Sartore-Bianchi3, Federica Di Nicolantonio1,4, Salvatore Siena3, Alberto Bardelli1,4
1Candiolo Cancer Institute – FPO, IRCCS, Str prov 142 Km 3.95, 10060 Candiolo, Torino, Italy
2FIRC Institute of Molecular Oncology (IFOM), Via Adamello, 16, 20139, Milan, Italy
3Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, Piazza Ospedale Maggiore 3, 20162, Milan, Italy
4University of Torino, Department of Oncology, Strada Provinciale, 142 km 3.95, 10060 Candiolo, Torino, Italy

Tóm tắt

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.

Tài liệu tham khảo

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Molecular Oncology

Tập 8

1084-1094

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