Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab
By K. Yonesaka, K. Zejnullahu, I. Okamoto, T. Satoh, F. Cappuzzo, J. Souglakos, D. Ercan, Andrew H. Rogers, M. Roncalli, M. Takeda and 22 more. Science Translational Medicine, 2011
661 citations recorded by the source corpus.
Several cancers become resistant to cetuximab by activating a bypass signaling pathway and preventing cetuximab inhibition of ERK1/2-stimulated growth. Combating Resistance to an EGF Receptor Inhibitor Many promising anticancer drugs are effective only for a limited time, because the tumor cells develop resistance. Cetuximab, directed against the epidermal growth factor receptor (EGFR), is no exception, and patients with colorectal, head and neck, or non–small cell lung cancer eventually cease to respond to the drug. Yonesaka and colleagues have determined that cetuximab-resistant cancer cells—both in culture and in patients—can up-regulate signaling through the ERBB2 growth factor receptor in several ways, permanently turning on extracellular signal–regulated kinase 1/2 (ERK1/2)–mediated growth, differentiation, and survival. They further show that interference with the ERBB2 pathway restores the ability of cetuximab to control these cancers, pointing to a promising resistance-fighting approach. The authors generated clones of cetuximab-resistant non–small cell lung and colorectal cancer cell lines by exposing the cells to increasing concentration of the drug. In some of these resistant clones, the ERBB2 receptor oncogene was genetically amplified, resulting in activated ERK1/2 signaling. Down-regulation of ERBB2 with a small interfering RNA or antibody restored sensitivity. Other clones did not have amplified ERBB2 genes but did make excess heregulin, an activating ligand for the ERBB2 receptor. Heregulin depletion or ERBB2 inhibition restored cetuximab sensitivity. After replicating these studies in xenografts in mice, the authors also looked for evidence that these resistance-associated alterations pertain to human tumors. In several groups of patients with colorectal cancer, they saw decreased survival or decreased sensitivity to cetuximab in those who exhibited amplified ERBB2 gene or higher heregulin concentrations. The concordance of their cellular data with patient experience improves confidence that concomitant treatment of certain lung, head and neck, or colorectal cancers with cetuximab and an anti-ERBB2 drug may prevent or delay the development of drug resistance. These studies add to other successes for this approach, which has also been used for analysis of other molecular targeted therapies, including EGFR kinase inhibitors. Cetuximab, an antibody directed against the epidermal growth factor receptor, is an effective clinical therapy for patients with colorectal, head and neck, and non–small cell lung cancer, particularly for those with KRAS and BRAF wild-type cancers. Treatment in all patients is limited eventually by the development of acquired resistance, but little is known about the underlying mechanism. Here, we show that activation of ERBB2 signaling in cell lines, either through ERBB2 amplification or through heregulin up-regulation, leads to persistent extracellular signal–regulated kinase 1/2 signaling and consequently to cetuximab resistance. Inhibition of ERBB2 or disruption of ERBB2/ERBB3 heterodimerization restores cetuximab sensitivity in vitro and in vivo. A subset of colorectal cancer patients who exhibit either de novo or acquired resistance to cetuximab-based therapy has ERBB2 amplification or high levels of circulating heregulin. Collectively, these findings identify two distinct resistance mechanisms, both of which promote aberrant ERBB2 signaling, that mediate cetuximab resistance. Moreover, these results suggest that ERBB2 inhibitors, in combination with cetuximab, represent a rational therapeutic strategy that should be assessed in patients with cetuximab-resistant cancers.
Subfields: Oncology, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/8e7e1bb4b406e8a453022a85458f4e96391b2912
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Citations in the corpus
- HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation. (2012, background): “Activation of HER2 signaling was recently reported to cause resistance to cetuximab alone in patients with colorectal cancer (28, 29).”
- Target Binding Properties and Cellular Activity of Afatinib (BIBW 2992), an Irreversible ErbB Family Blocker (2012, background): “De novo or acquired resistance to cetuximab can develop through receptor mutations (S492R; Montagut et al., 2012), ErbB2 amplification and increased heregulin synthesis (Yonesaka et al., 2011), or generation of HER2 isoforms by alternative splicing (e.g., 611-CTF; Quesnelle and Grandis, 2011).”
- Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer (2013, neutral): “Multiple mechanisms of secondary resistance to anti-EGFR antibodies have been reported, such as expression of EGFR ligands, HER2 amplification and deregulation of the EGFR recycling process (12–16).”
- ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. (2016, background): “There is no clear evidence for HER3 overexpression and HER3 mutations, mesenchymal– epidermal transition (MET)/MET alterations (overexpression or gene amplification) or KRAS amplification, EGFR mutations [tyrosine kinase (TK) or ligand-binding domains] or amplification in the resistance to EGFR anti”