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

doi:10.1038/s41467-020-16952-9

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 Journal › Article › Academic › peer-review

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.

Original language	English
Article number	3157
Pages (from-to)	3157
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-16952-9
Publication status	Published - 22 Jun 2020

Funding

We thank A. Bardelli (Torino, Italy) for gift of cell lines, the facilities of The Netherlands Cancer Institute: Mouse Clinic–Intervention Unice (Natalie Proost, Bjorn Siteur, Bas van Gerwen, Charlotte Baak, Renske Grimmerink, Rebecca Theeuwsen and Marieke van de Ven), Robotics and Screening Center (Ben Morris and Roderick Bei-jersbergen), Clinical Pharmacology (Levi Buil and Artur Burylo), Experimental Animal Pathology, Flow Cytometry and Sequencing. We also thank Richard Marais for discussions. This work was supported by a grant from the Dutch Cancer Society through the Oncode Institute. Al.V. was supported by the Fondo de Investigaciones Sanitarias, FIS (PI16-01898, and by the Spanish Association Against Cancer, AECC (CGB14142035THOM) and Ideas Semilla project (IDEAS098VILL-IDEAS16) and Generalitat de Catalunya (2014SGR364). L.F. received a European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie, grant agreement number 799850. E.N. was funded by Instituto Carlos III through the project PI18/00920. We thank CERCA Program/Generalitat de Catalunya for their institutional support and grant 2017SGR448.

Funders	Funder number
Dutch Cancer Society
Fondo de Investigaciones Sanitarias	PI16-01898
Marie Sklodowska-Curie
Oncode Institute
Spanish Association Against Cancer
Albert Einstein Cancer Center	IDEAS098VILL-IDEAS16, CGB14142035THOM
Horizon 2020 Framework Programme	799850
Generalitat de Catalunya	2014SGR364
Instituto de Salud Carlos III	PI18/00920

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Fernandes Neto, J. M., Nadal, E., Bosdriesz, E., Ooft, S. N., Farre, L., McLean, C., Klarenbeek, S., Jurgens, A., Hagen, H., Wang, L., Felip, E., Martinez-Marti, A., Vidal, A., Voest, E., Wessels, L. F. A., van Tellingen, O., Villanueva, A., & Bernards, R. (2020). Multiple low dose therapy as an effective strategy to treat EGFR inhibitor-resistant NSCLC tumours. Nature Communications, 11(1), 3157. Article 3157. https://doi.org/10.1038/s41467-020-16952-9

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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.",

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Fernandes Neto, JM, Nadal, E, Bosdriesz, E, Ooft, SN, Farre, L, McLean, C, Klarenbeek, S, Jurgens, A, Hagen, H, Wang, L, Felip, E, Martinez-Marti, A, Vidal, A, Voest, E, Wessels, LFA, van Tellingen, O, Villanueva, A & Bernards, R 2020, 'Multiple low dose therapy as an effective strategy to treat EGFR inhibitor-resistant NSCLC tumours', Nature Communications, vol. 11, no. 1, 3157, pp. 3157. https://doi.org/10.1038/s41467-020-16952-9

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AU - Fernandes Neto, João M

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AU - McLean, Chelsea

AU - Klarenbeek, Sjoerd

AU - Jurgens, Anouk

AU - Hagen, Hannes

AU - Wang, Liqin

AU - Felip, Enriqueta

AU - Martinez-Marti, Alex

AU - Vidal, August

AU - Voest, Emile

AU - Wessels, Lodewyk F A

AU - van Tellingen, Olaf

AU - Villanueva, Alberto

AU - Bernards, René

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

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