Cetuximab, an epidermal growth factor receptor (EGFR)-directed antibody, is an effective treatment of patients with colorectal cancer (CRC), head and neck squamous cell cancer (HNSCC), and non-small cell lung cancer (NSCLC). However, in such a promising drug, tumor cells eventually develop the resistance to cetuximab after initial response. Recently, we uncovered the mechanism of acquired resistance to cetuximab, which is caused by ERBB2 activation through whether ERBB2 genomic amplification or ligand (heregulin) overexpression (Science Translational Medicine 2011).
At first we established cetuximab-resistant clones of NSCLC and CRC cell line. Genome-wide copy number analyses revealed that ERBB2 oncogene was genetically amplified in those cetuximab-resistant clones. ERBB2 inhibition with trastuzmab or lapatinib could restore the sensitivity to cetuximab in these clones. In CRC patients treated with cetuximab (n = 233), patients with ERRB2 amplified (n = 13) had significantly shorter overall survival compared with patients with ERBB2 non-amplified. ERBB2 amplification was detected in tissue samples post-treatment in patients who acquired resistance to cetuximab.
Secondary, we identified ‘heregulin’ also could lead to cetuximab resistance. Heregulin is ERBB3 ligand and preferentially induces the hetero-dimerization between ERBB2 and ERBB3. Similarly, ERBB2 was activated by heregulin. Thus we observed that heregulin could induce cetuximab resistance in vitro and in vivo. CRC patients with high expression of heregulin were significantly resistant to cetuximab, and had significantly shorter PFS and OS in cetuximab treatment. Moreover, plasma samples from patients, who acquired cetuximab resistance, had significantly higher expression of heregulin compared with pre-treatment.
Our findings suggest ERBB2 activation induced both de novo and acquired resistance to cetuximab. Most importantly ERBB2 (or ERBB3) inhibitor combination therapy may conquer the cetuximab resistance. Actually clinical trials are now on-going evaluating ERBB2 or ERBB3 inhibitor combined with cetuximab. As another remaining issue, ERBB2 or heregulin could be biomarker for patient selection. West Japan Oncology Group (WJOG) is now prospectively evaluating these biomarkers in mCRC patients in clinical trial (WJOG6210G).