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

Sabrina Arena, Giulia Siravegna, Benedetta Mussolin, Jeffrey D. Kearns, Beni B. Wolf, Sandra Misale, Luca Lazzari, Andrea Bertotti, Livio Trusolino, Alex Adjei, Clara Montagut, Federica Di Nicolantonio, Rachel Nering, Alberto Bardelli

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number324ra14
JournalScience Translational Medicine
Volume8
Issue number324
DOIs
StatePublished - Feb 3 2016
Externally publishedYes

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Epidermal Growth Factor Receptor
Colorectal Neoplasms
Mutation
Antibodies
Cetuximab
MM-151
panitumumab
Circulating Neoplastic Cells
Drug Resistance
Recurrence
DNA
Growth

ASJC Scopus subject areas

  • Medicine(all)

Cite this

MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancers harboring EGFR extracellular domain mutations. / Arena, Sabrina; Siravegna, Giulia; Mussolin, Benedetta; Kearns, Jeffrey D.; Wolf, Beni B.; Misale, Sandra; Lazzari, Luca; Bertotti, Andrea; Trusolino, Livio; Adjei, Alex; Montagut, Clara; Di Nicolantonio, Federica; Nering, Rachel; Bardelli, Alberto.

In: Science Translational Medicine, Vol. 8, No. 324, 324ra14, 03.02.2016.

Research output: Contribution to journalArticle

Arena, S, Siravegna, G, Mussolin, B, Kearns, JD, Wolf, BB, Misale, S, Lazzari, L, Bertotti, A, Trusolino, L, Adjei, A, Montagut, C, Di Nicolantonio, F, Nering, R & Bardelli, A 2016, 'MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancers harboring EGFR extracellular domain mutations', Science Translational Medicine, vol. 8, no. 324, 324ra14. https://doi.org/10.1126/scitranslmed.aad5640
Arena, Sabrina ; Siravegna, Giulia ; Mussolin, Benedetta ; Kearns, Jeffrey D. ; Wolf, Beni B. ; Misale, Sandra ; Lazzari, Luca ; Bertotti, Andrea ; Trusolino, Livio ; Adjei, Alex ; Montagut, Clara ; Di Nicolantonio, Federica ; Nering, Rachel ; Bardelli, Alberto. / MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancers harboring EGFR extracellular domain mutations. In: Science Translational Medicine. 2016 ; Vol. 8, No. 324.
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