Study points to new strategy to overcome cetuximab resistance

9 Sep 2011

Inhibition of the ERBB2 receptor oncogene restored cetuximab sensitivity both in vitro and invivo, reports an international study published in Science Translational Medicine.

Many promising anticancer drugs are effective only for a limited time because tumour cells develop resistance. Cetuximab, an antibody directed against the epidermal growth factor receptor (EGFR), has proved no exception, with colorectal, head and neck or non-small cell lung cancer patients commonly ceasing to respond to treatment after a year.

In the current study Kimio Yonesaka , from Kiniki University School of Medicine (Osaka, Japan),and Pasi Janne from Dana-Farber Cancer Research Institute (Boston, US) generated clones of cetuximab-resistant non-small cell lung and colorectal cancer cell lines by exposing the cells to increasing concentrations of cetuximab.

In some of these resistant clones, the ERBB2 receptor oncogene was shown to be genetically amplified. It appeared that ERBB2 was actively sending "grow" signals that circumvented the "stop growing" signals triggered by cetuximab.

The investigators were able to show that down-regulation of ERBB2 with an interfering RNA or antibody restored sensitivity. In several groups of patients with colorectal cancer, the team saw decreased survival or decreased sensitivity to cetuximab in those who exhibited amplified ERBB2 genes.

The findings, say the authors, suggest that combining cetuximab with ERBB2-inhibiting drugs could be an effective therapy for cancers that are cetuximab-resistant from the start or for those that become resistant over time. Several such ERBB2 inhibitors have already been approved.



K Yonesaka, K Zejnullahu, I Okamoto, et al. Activation of ERBB2 Signaling Causes Resistance to the EGFR-Directed Therapeutic Antibody Cetuximab.  Science Translational Medicine.  DOI: 10.1126/scitranslmed.3002442.