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. [email protected] [email protected].
  • 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. [email protected] [email protected].
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