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

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 Martinez-Marti, August Vidal, Emile Voest, Lodewyk F. A. Wessels, Olaf van Tellingen, Alberto Villanueva and René Bernards ()
Additional contact information
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
Salo N. Ooft: The Netherlands Cancer Institute
Lourdes Farre: Subprogram Against Cancer Therapeutic Resistance (ProCURE), ICO, Oncobell Program, IDIBELL, L’Hospitalet del Llobregat
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)
Alex Martinez-Marti: Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology (VHIO)
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
René Bernards: Plesmanlaan 121

Nature Communications, 2020, vol. 11, issue 1, 1-9

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16952-9

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