Acquired resistance to EGFR‐targeted therapies in colorectal cancer

Abstract

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.

The MET Inhibitor AZD6094 (Savolitinib, HMPL-504) Induces Regression in Papillary Renal Cell Carcinoma Patient–Derived Xenograft Models

“…Interestingly, MET amplification was also detected in up to 22% of clinical specimen of gefitinib-or erlotinib-resistant lung cancer patients (32). In colorectal cancer, MET amplification has been linked to de novo and acquired resistance of cetuximab with cetuximab-resistant tumor models retaining single agent or combination activity to crizotinib or the MET inhibitor JNJ-38877605 (33,34). Also, MET and HGF overexpression can occur in the absence of gene amplification as described in renal, thyroid, and ovarian cancers (4,35,36).…”

Maintenance Treatment with Cetuximab and BAY86-9766 Increases Antitumor Efficacy of Irinotecan plus Cetuximab in Human Colorectal Cancer Xenograft Models

“…The idea of this in vivo study has been founded on two considerations: first that mechanisms of acquired resistance to anti-EGFR inhibitors in the treatment of metastatic colorectal cancer are extremely heterogeneous ranging from genetic mutations of the EGFR-RAS-RAF-MEK to activation of independent pathways driven by other tyrosine kinases receptors (RTK; refs. 40,41). This suggests that the concomitant blockade of signaling nodes that could confer resistance to anti-EGFR inhibitors might be a possible strategy to overcome it.…”

MET/HGF pathway activation as a paradigm of resistance to targeted therapies

“…Additionally, there is no specific genetic defect being targeted in this setting. For example, Van Emburgh and colleagues reported that in vitro stimulation of MET by HGF led to resistance in CRC cells and xenografts to cetuximab and panitumumab and 3 out of 7 patients with acquired resistance to EGFR-directed therapy were noted to have MET amplification (45). Pharmacological silencing of the MET pathway in preclinical models led to reconstitution of sensitivity.…”