Multiple low dose therapy as an effective strategy to treat EGFR inhibitor-resistant NSCLC tumours.
Animals
Antineoplastic Agents
/ administration & dosage
Carcinoma, Non-Small-Cell Lung
/ drug therapy
Cell Line, Tumor
Cell Proliferation
/ drug effects
Drug Resistance, Neoplasm
/ genetics
ErbB Receptors
/ genetics
Humans
Lung Neoplasms
/ drug therapy
MAP Kinase Signaling System
/ drug effects
Mice
Models, Animal
Mutation
Protein Kinase Inhibitors
/ administration & dosage
Tumor Cells, Cultured
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
22 06 2020
22 06 2020
Historique:
received:
28
10
2019
accepted:
04
06
2020
entrez:
24
6
2020
pubmed:
24
6
2020
medline:
29
8
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32572029
doi: 10.1038/s41467-020-16952-9
pii: 10.1038/s41467-020-16952-9
pmc: PMC7308397
doi:
Substances chimiques
Antineoplastic Agents
0
Protein Kinase Inhibitors
0
EGFR protein, mouse
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
Banques de données
figshare
['10.6084/m9.figshare.12408803.v1']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3157Références
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