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.

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

ARENA, Sabrina
First
;
SIRAVEGNA, GIULIA;MISALE, SANDRA;LAZZARI, LUCA;BERTOTTI, Andrea;TRUSOLINO, Livio;DI NICOLANTONIO, Federica;BARDELLI, Alberto
Last
2016

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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324ra14
http://stm.sciencemag.org/content/scitransmed/8/324/324ra14.full.pdf
Medicine (all)
Arena, Sabrina; Siravegna, Giulia; Mussolin, Benedetta; Kearns, Jeffrey D.; Wolf, Beni B.; Misale, Sandra; Lazzari, Luca; Bertotti, Andrea; Trusolino, Livio; Adjei, Alex A.; Montagut, Clara; Di Nicolantonio, Federica; Nering, Rachel; Bardelli, Alberto
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1559473
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