2. Academic Validation
  3. MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancers harboring EGFR extracellular domain mutations

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

  • Sci Transl Med. 2016 Feb 3;8(324):324ra14. doi: 10.1126/scitranslmed.aad5640.
Sabrina Arena 1,  Giulia Siravegna 2,  Benedetta Mussolin 3,  Jeffrey D Kearns 4,  Beni B Wolf 4,  Sandra Misale 3,  Luca Lazzari 2,  Andrea Bertotti 2,  Livio Trusolino 2,  Alex A Adjei 5,  Clara Montagut 6,  Federica Di Nicolantonio 2,  Rachel Nering 4,  Alberto Bardelli 7
Affiliations

Affiliations

  • 1 Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia (FPO), IRCCS, Candiolo, Torino 10060, Italy. FIRC Institute of Molecular Oncology (IFOM), Milano 20139, Italy. Department of Oncology, University of Torino, Candiolo, Torino 10060, Italy. sabrina.arena@ircc.it alberto.bardelli@unito.it.
  • 2 Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia (FPO), IRCCS, Candiolo, Torino 10060, Italy. Department of Oncology, University of Torino, Candiolo, Torino 10060, Italy.
  • 3 Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia (FPO), IRCCS, Candiolo, Torino 10060, Italy.
  • 4 Merrimack Pharmaceuticals Inc., Cambridge, MA 02139, USA.
  • 5 Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
  • 6 Medical Oncology Department, Hospital del Mar, Barcelona 08003, Spain. Cancer Research Program, FIMIM (Hospital del Mar Medical Research Institute), Hospital del Mar, Barcelona 08003, Spain.
  • 7 Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia (FPO), IRCCS, Candiolo, Torino 10060, Italy. Department of Oncology, University of Torino, Candiolo, Torino 10060, Italy. sabrina.arena@ircc.it alberto.bardelli@unito.it.
PMID: 26843189 DOI: 10.1126/scitranslmed.aad5640
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-P991572
    Anti-EGFR Antibody