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, René Bernards

Research output: Contribution to JournalArticleAcademicpeer-review


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.

Original languageEnglish
Article number3157
Pages (from-to)3157
JournalNature Communications
Issue number1
Publication statusPublished - 22 Jun 2020


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