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Title: Multiple low dose therapy as an effective strategy to treat EGFR inhibitor-resistant NSCLC tumours
Author: Fernandes Neto, João M.
Nadal, Ernest
Bosdriesz, Evert
Ooft, Salo N.
Farré, Lourdes
McLean, Chelsea
Klarenbeek, Sjoerd
Jurgens, Anouk
Hagen, Hannes
Wang, Liqin
Felip, Enriqueta
Martínez Martí, Alex
Vidal-Bel, August
Voest, Emile
Wessels, Lodewyk F. A.
van Tellingen, Olaf
Villanueva Garatachea, Alberto
Bernards, René
Keywords: Resistència als medicaments
Drug resistance
Issue Date: 22-Jun-2020
Citation: Neto, J. M. F., Nadal, E., Bosdriesz, E., Ooft, S. N., Farre, L., McLean, C., ... & Felip, E. (2020). Multiple low dose therapy as an effective strategy to treat EGFR inhibitor-resistant NSCLC tumours. Nature Communications, 11(1), 1-9.
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) inhibidor 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 inhibidor therapy.
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It is part of: Nature Communications, 2020, vol. 11, num. 1, pp. 1-9
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Appears in Collections:Articles publicats en revistes (Patologia i Terapèutica Experimental)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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