Major finding: An acquired EGFR mutation can block cetuximab binding and confer drug resistance.
Clinical relevance: These findings support the clinical use of panitumumab after cetuximab failure.
Impact: Resistance to therapeutic antibodies can arise through epitope mutation.
Through unknown mechanisms, metastatic colorectal cancers ultimately acquire resistance to cetuximab and panitumumab, 2 antibodies targeting EGFR that have been shown to prolong survival in patients. To identify the underlying causes of cetuximab resistance, Montagut and colleagues continuously treated cetuximab-sensitive, EGFR-amplified human metastatic colorectal cancer cells with cetuximab for 5 months and isolated resistant clones. Surprisingly, these cells did not activate other receptor tyrosine kinases or acquire mutations in other oncogenes frequently mutated in metastatic colorectal cancers, and the cells were still highly sensitive to EGFR inhibition by panitumumab or gefitinib. The authors therefore hypothesized that a mutation had occurred in the EGFR cetuximab-binding epitope, and sequencing revealed that all resistant clones had acquired a S492R mutation within the ectodomain which likely interferes with cetuximab binding. Flow cytometry and in vitro binding studies confirmed that cetuximab binding by the EGFR S492R mutant was severely impaired, but binding to panitumumab was unaffected. To determine whether the EGFR S492R mutation contributed to acquired cetuximab resistance in a clinical setting, the authors sequenced EGFR in pre- and posttherapy biopsies from 10 patients whose disease progressed after an initial response to cetuximab. Two patients had acquired 2 different somatic EGFR mutations that both resulted in the S492R amino acid substitution. Based on the identification of this mutation and the preclinical data, the patient that was still alive was treated with panitumumab and experienced a more than 50% reduction in his liver metastases before showing signs of disease progression 5 months later. These findings establish epitope mutation as a possible mechanism of resistance to therapeutic antibodies and suggest that panitumumab treatment may be effective after cetuximab failure.
Montagut C, Dalmases A, Bellosillo B, Crespo M, Pairet S, Iglesias M, et al. Identification of a mutation in the extracellular domain of the epidermal growth factor receptor conferring cetuximab resistance in colorectal cancer. Nat Med 2012;18:221–3.
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