Research ArticleCancer

MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancers harboring EGFR extracellular domain mutations

Science Translational Medicine  03 Feb 2016:
Vol. 8, Issue 324, pp. 324ra14
DOI: 10.1126/scitranslmed.aad5640

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The more the merrier

Monoclonal antibodies against the epidermal growth factor receptor (EGFR), which drives cancer growth, are frequently used in colorectal cancer. Unfortunately, the cancers commonly develop drug-resistant mutations, and the monoclonal antibodies become ineffective. To overcome this problem, Arena et al. used an oligoclonal mixture of monoclonal antibodies called MM-151, which binds multiple parts of the EGFR molecule at once, so that the cancer cannot develop resistance by mutating one site at a time. The authors demonstrated that this approach is effective in both preclinical models and patients who were resistant to other anti-EGFR therapies, paving the way for further clinical development of the oligoclonal antibody.

Abstract

The anti–epidermal growth factor receptor (EGFR) antibodies cetuximab and panitumumab are used to treat RAS wild-type colorectal cancers (CRCs), but their efficacy is limited by the emergence of acquired drug resistance. After EGFR blockade, about 20% of CRCs develop mutations in the EGFR extracellular domain (ECD) that impair antibody binding and are associated with clinical relapse. We hypothesized that EGFR ECD–resistant variants could be targeted by the recently developed oligoclonal antibody MM-151 that binds multiple regions of the EGFR ECD. MM-151 inhibits EGFR signaling and cell growth in preclinical models, including patient-derived cells carrying mutant EGFR. Upon MM-151 treatment, EGFR ECD mutations decline in circulating cell-free tumor DNA (ctDNA) of CRC patients who previously developed resistance to EGFR blockade. These data provide molecular rationale for the clinical use of MM-151 in patients who become resistant to cetuximab or panitumumab as a result of EGFR ECD mutations.

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