TY - JOUR
T1 - MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancers harboring EGFR extracellular domain mutations
AU - Arena, Sabrina
AU - Siravegna, Giulia
AU - Mussolin, Benedetta
AU - Kearns, Jeffrey D.
AU - Wolf, Beni B.
AU - Misale, Sandra
AU - Lazzari, Luca
AU - Bertotti, Andrea
AU - Trusolino, Livio
AU - Adjei, Alex A.
AU - Montagut, Clara
AU - Di Nicolantonio, Federica
AU - Nering, Rachel
AU - Bardelli, Alberto
N1 - S. Arena non risulta correttamente affiliata in questa pubblicazione
PY - 2016/2/3
Y1 - 2016/2/3
N2 - 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.
AB - 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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U2 - 10.1126/scitranslmed.aad5640
DO - 10.1126/scitranslmed.aad5640
M3 - Article
AN - SCOPUS:84958078144
VL - 8
JO - Science Translational Medicine
JF - Science Translational Medicine
SN - 1946-6234
IS - 324
M1 - 324ra14
ER -