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Multiple low dose therapy as an effective strategy to treat EGFR inhibitor-resistant NSCLC tumours

Author

Listed:
  • João M. Fernandes Neto

    (Plesmanlaan 121)

  • Ernest Nadal

    (Subprogram Against Cancer Therapeutic Resistance (ProCURE), ICO, Oncobell Program, IDIBELL, L’Hospitalet del Llobregat)

  • Evert Bosdriesz

    (Plesmanlaan 121
    Vrije Universiteit)

  • Salo N. Ooft

    (The Netherlands Cancer Institute)

  • Lourdes Farre

    (Subprogram Against Cancer Therapeutic Resistance (ProCURE), ICO, Oncobell Program, IDIBELL, L’Hospitalet del Llobregat
    Fundaçao Oswaldo Cruz (FIOCRUZ))

  • Chelsea McLean

    (The Netherlands Cancer Institute)

  • Sjoerd Klarenbeek

    (The Netherlands Cancer Institute)

  • Anouk Jurgens

    (Plesmanlaan 121)

  • Hannes Hagen

    (Plesmanlaan 121)

  • Liqin Wang

    (Plesmanlaan 121)

  • Enriqueta Felip

    (Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology (VHIO)
    Autonomous University of Barcelona (UAB))

  • Alex Martinez-Marti

    (Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology (VHIO)
    Autonomous University of Barcelona (UAB))

  • August Vidal

    (Subprogram Against Cancer Therapeutic Resistance (ProCURE), ICO, Oncobell Program, IDIBELL, L’Hospitalet del Llobregat)

  • Emile Voest

    (The Netherlands Cancer Institute)

  • Lodewyk F. A. Wessels

    (Plesmanlaan 121)

  • Olaf van Tellingen

    (The Netherlands Cancer Institute)

  • Alberto Villanueva

    (Subprogram Against Cancer Therapeutic Resistance (ProCURE), ICO, Oncobell Program, IDIBELL, L’Hospitalet del Llobregat
    Bellvitge Health Science Campus)

  • René Bernards

    (Plesmanlaan 121)

Abstract

Resistance to targeted cancer drugs is thought to result from selective pressure exerted by a high drug dose. Partial inhibition of multiple components in the same oncogenic signalling pathway may add up to complete pathway inhibition, while decreasing the selective pressure on each component to acquire a resistance mutation. We report here testing of this Multiple Low Dose (MLD) therapy model in EGFR mutant NSCLC. We show that as little as 20% of the individual effective drug doses is sufficient to completely block MAPK signalling and proliferation when used in 3D (RAF + MEK + ERK) or 4D (EGFR + RAF + MEK + ERK) inhibitor combinations. Importantly, EGFR mutant NSCLC cells treated with MLD therapy do not develop resistance. Using several animal models, we find durable responses to MLD therapy without associated toxicity. Our data support the notion that MLD therapy could deliver clinical benefit, even for those having acquired resistance to third generation EGFR inhibitor therapy.

Suggested Citation

  • João M. Fernandes Neto & Ernest Nadal & Evert Bosdriesz & Salo N. Ooft & Lourdes Farre & Chelsea McLean & Sjoerd Klarenbeek & Anouk Jurgens & Hannes Hagen & Liqin Wang & Enriqueta Felip & Alex Martine, 2020. "Multiple low dose therapy as an effective strategy to treat EGFR inhibitor-resistant NSCLC tumours," Nature Communications, Nature, vol. 11(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16952-9
    DOI: 10.1038/s41467-020-16952-9
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