title: MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancers harboring EGFR extracellular domain mutations.
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.
authors: 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.
authors: Sabrina
authors: S
authors: Arena
authors: 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.
authors: Giulia
authors: G
authors: Siravegna
authors: Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia (FPO), IRCCS, Candiolo, Torino 10060, Italy.
authors: Benedetta
authors: B
authors: Mussolin
authors: Merrimack Pharmaceuticals Inc., Cambridge, MA 02139, USA.
authors: Jeffrey D
authors: JD
authors: Kearns
authors: Merrimack Pharmaceuticals Inc., Cambridge, MA 02139, USA.
authors: Beni B
authors: BB
authors: Wolf
authors: Candiolo Cancer Institute-Fondazione del Piemonte per l'Oncologia (FPO), IRCCS, Candiolo, Torino 10060, Italy.
authors: Sandra
authors: S
authors: Misale
authors: 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.
authors: Luca
authors: L
authors: Lazzari
authors: 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.
authors: Andrea
authors: A
authors: Bertotti
authors: 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.
authors: Livio
authors: L
authors: Trusolino
authors: Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors: Alex A
authors: AA
authors: Adjei
authors: 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.
authors: Clara
authors: C
authors: Montagut
authors: 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.
authors: Federica
authors: F
authors: Di Nicolantonio
authors: Merrimack Pharmaceuticals Inc., Cambridge, MA 02139, USA.
authors: Rachel
authors: R
authors: Nering
authors: 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.
authors: Alberto
authors: A
authors: Bardelli
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D002474:Cell-Free System; D000068818:Cetuximab / Q000494:pharmacology / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D004273:DNA, Neoplasm / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D000939:Epitopes / Q000737:chemistry; D066246:ErbB Receptors / Q000737:chemistry / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D009154:Mutation / Q000235:genetics*; D000077544:Panitumumab; D000072417:Protein Domains; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D004273:DNA, Neoplasm; D000939:Epitopes; D008024:Ligands; C000607291:MM-151; D000077544:Panitumumab; D066246:ErbB Receptors; D000068818:Cetuximab