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Acquired RAS or EGFR mutations and duration of response to EGFR blockade in colorectal cancer

Author

Listed:
  • Beth O. Van Emburgh

    (Candiolo Cancer Institute—FPO, IRCCS
    FIRC Institute of Molecular Oncology (IFOM)
    University of Torino)

  • Sabrina Arena

    (Candiolo Cancer Institute—FPO, IRCCS
    University of Torino)

  • Giulia Siravegna

    (Candiolo Cancer Institute—FPO, IRCCS
    University of Torino)

  • Luca Lazzari

    (Candiolo Cancer Institute—FPO, IRCCS
    University of Torino)

  • Giovanni Crisafulli

    (Candiolo Cancer Institute—FPO, IRCCS
    University of Torino)

  • Giorgio Corti

    (Candiolo Cancer Institute—FPO, IRCCS)

  • Benedetta Mussolin

    (Candiolo Cancer Institute—FPO, IRCCS)

  • Federica Baldi

    (Candiolo Cancer Institute—FPO, IRCCS
    University of Torino)

  • Michela Buscarino

    (Candiolo Cancer Institute—FPO, IRCCS)

  • Alice Bartolini

    (Candiolo Cancer Institute—FPO, IRCCS)

  • Emanuele Valtorta

    (Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda)

  • Joana Vidal

    (Hospital del Mar
    Cancer Research Program, FIMIM (Hospital del Mar Medical Research Institute), Hospital del Mar)

  • Beatriz Bellosillo

    (Cancer Research Program, FIMIM (Hospital del Mar Medical Research Institute), Hospital del Mar
    Hospital del Mar)

  • Giovanni Germano

    (Candiolo Cancer Institute—FPO, IRCCS)

  • Filippo Pietrantonio

    (Fondazione IRCCS Istituto Nazionale dei Tumori)

  • Agostino Ponzetti

    (Colorectal Cancer Unit, San Giovanni Battista Hospital)

  • Joan Albanell

    (Hospital del Mar
    Cancer Research Program, FIMIM (Hospital del Mar Medical Research Institute), Hospital del Mar)

  • Salvatore Siena

    (Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda
    Università degli Studi di Milano)

  • Andrea Sartore-Bianchi

    (Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda)

  • Federica Di Nicolantonio

    (Candiolo Cancer Institute—FPO, IRCCS
    University of Torino)

  • Clara Montagut

    (Hospital del Mar
    Cancer Research Program, FIMIM (Hospital del Mar Medical Research Institute), Hospital del Mar)

  • Alberto Bardelli

    (Candiolo Cancer Institute—FPO, IRCCS
    University of Torino)

Abstract

Blockade of the epidermal growth factor receptor (EGFR) with the monoclonal antibodies cetuximab or panitumumab is effective in a subset of colorectal cancers (CRCs), but the emergence of resistance limits the efficacy of these therapeutic agents. At relapse, the majority of patients develop RAS mutations, while a subset acquires EGFR extracellular domain (ECD) mutations. Here we find that patients who experience greater and longer responses to EGFR blockade preferentially develop EGFR ECD mutations, while RAS mutations emerge more frequently in patients with smaller tumour shrinkage and shorter progression-free survival. In circulating cell-free tumour DNA of patients treated with anti-EGFR antibodies, RAS mutations emerge earlier than EGFR ECD variants. Subclonal RAS but not EGFR ECD mutations are present in CRC samples obtained before exposure to EGFR blockade. These data indicate that clonal evolution of drug-resistant cells is associated with the clinical outcome of CRC patients treated with anti-EGFR antibodies.

Suggested Citation

  • Beth O. Van Emburgh & Sabrina Arena & Giulia Siravegna & Luca Lazzari & Giovanni Crisafulli & Giorgio Corti & Benedetta Mussolin & Federica Baldi & Michela Buscarino & Alice Bartolini & Emanuele Valto, 2016. "Acquired RAS or EGFR mutations and duration of response to EGFR blockade in colorectal cancer," Nature Communications, Nature, vol. 7(1), pages 1-9, December.
  • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13665
    DOI: 10.1038/ncomms13665
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    Cited by:

    1. Radia M. Johnson & Xueping Qu & Chu-Fang Lin & Ling-Yuh Huw & Avinashnarayan Venkatanarayan & Ethan Sokol & Fang-Shu Ou & Nnamdi Ihuegbu & Oliver A. Zill & Omar Kabbarah & Lisa Wang & Richard Bourgon , 2022. "ARID1A mutations confer intrinsic and acquired resistance to cetuximab treatment in colorectal cancer," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Xinlei Zhuang & Zhe Wang & Jiansheng Fan & Xuefei Bai & Yingchun Xu & James J. Chou & Tingjun Hou & Shuqing Chen & Liqiang Pan, 2022. "Structure-guided and phage-assisted evolution of a therapeutic anti-EGFR antibody to reverse acquired resistance," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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