MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancers harboring EGFR extracellular domain mutations.
Sci Transl Med
; 8(324): 324ra14, 2016 Feb 03.
Article
in En
| MEDLINE
| ID: mdl-26843189
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Colorectal Neoplasms
/
Drug Resistance, Neoplasm
/
ErbB Receptors
/
Cetuximab
/
Antibodies, Monoclonal
/
Mutation
Type of study:
Prognostic_studies
Limits:
Humans
Language:
En
Journal:
Sci Transl Med
Journal subject:
CIENCIA
/
MEDICINA
Year:
2016
Type:
Article