Multiple low dose therapy as an effective strategy to treat EGFR inhibitor-resistant NSCLC tumours
Fernandes Neto, João M. (The Netherlands Cancer Institute (Amsterdam, Països Baixos))
Nadal, Ernest (Institut d'Investigació Biomèdica de Bellvitge)
Bosdriesz, Evert (Vrije Universiteit)
Ooft, Salo N. (The Netherlands Cancer Institute (Amsterdam, Països Baixos))
Farre, Lourdes (Fundação Oswaldo Cruz (Brasil))
McLean, Chelsea (The Netherlands Cancer Institute (Amsterdam, Països Baixos))
Klarenbeek, Sjoerd (The Netherlands Cancer Institute. Experimental Animal Pathology)
Jurgens, Anouk (The Netherlands Cancer Institute (Amsterdam, Països Baixos))
Hagen, Hannes (The Netherlands Cancer Institute (Amsterdam, Països Baixos))
Wang, Liqin (The Netherlands Cancer Institute (Amsterdam, Països Baixos))
Felip, Enriqueta (Universitat Autònoma de Barcelona)
Martinez-Marti, Alex (Universitat Autònoma de Barcelona)
Vidal, August (Institut d'Investigació Biomèdica de Bellvitge)
Voest, Emile (The Netherlands Cancer Institute (Amsterdam, Països Baixos))
Wessels, Lodewyk F. A. (The Netherlands Cancer Institute (Amsterdam, Països Baixos))
van Tellingen, Olaf (The Netherlands Cancer Institute (Amsterdam, Països Baixos))
Villanueva, Alberto (Hospital Universitari de Bellvitge)
Bernards, Rene (The Netherlands Cancer Institute (Amsterdam, Països Baixos))

Data:	2020
Resum:	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. A drug used at the maximum tolerated dose can exert a strong selective pressure on cancer cells leading to resistance. In this study, the authors demonstrate the efficacy of using low dose of multiple drugs for preventing and treating resistance to EGFR tyrosine kinase inhibitors in NSCLC cells.
Ajuts:	Ministerio de Economía y Competitividad PI16-01898 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014SGR364 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017SGR448 European Commission 799850
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Cancer ; Lung cancer
Publicat a:	Nature communications, Vol. 11 (june 2020) , ISSN 2041-1723

DOI: 10.1038/s41467-020-16952-9
PMID: 32572029

9 p, 1.8 MB

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