Resistance to targeted therapies as a multifactorial, gradual adaptation to inhibitor specific selective pressures.
Anaplastic Lymphoma Kinase
/ antagonists & inhibitors
Animals
Antineoplastic Agents
/ pharmacology
Carcinoma, Non-Small-Cell Lung
/ drug therapy
Drug Resistance, Neoplasm
/ drug effects
Epigenesis, Genetic
/ drug effects
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Lapatinib
/ pharmacology
Lung Neoplasms
/ drug therapy
Mice
Polymorphism, Single Nucleotide
/ drug effects
RNA-Seq
Single-Cell Analysis
Xenograft Model Antitumor Assays
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
14 05 2020
14 05 2020
Historique:
received:
16
01
2020
accepted:
17
04
2020
entrez:
16
5
2020
pubmed:
16
5
2020
medline:
1
9
2020
Statut:
epublish
Résumé
Despite high initial efficacy, targeted therapies eventually fail in advanced cancers, as tumors develop resistance and relapse. In contrast to the substantial body of research on the molecular mechanisms of resistance, understanding of how resistance evolves remains limited. Using an experimental model of ALK positive NSCLC, we explored the evolution of resistance to different clinical ALK inhibitors. We found that resistance can originate from heterogeneous, weakly resistant subpopulations with variable sensitivity to different ALK inhibitors. Instead of the commonly assumed stochastic single hit (epi) mutational transition, or drug-induced reprogramming, we found evidence for a hybrid scenario involving the gradual, multifactorial adaptation to the inhibitors through acquisition of multiple cooperating genetic and epigenetic adaptive changes. Additionally, we found that during this adaptation tumor cells might present unique, temporally restricted collateral sensitivities, absent in therapy naïve or fully resistant cells, suggesting the potential for new therapeutic interventions, directed against evolving resistance.
Identifiants
pubmed: 32409712
doi: 10.1038/s41467-020-16212-w
pii: 10.1038/s41467-020-16212-w
pmc: PMC7224215
doi:
Substances chimiques
Antineoplastic Agents
0
Lapatinib
0VUA21238F
ALK protein, human
EC 2.7.10.1
Anaplastic Lymphoma Kinase
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Video-Audio Media
Langues
eng
Sous-ensembles de citation
IM
Pagination
2393Subventions
Organisme : NCI NIH HHS
ID : K12 CA076917
Pays : United States
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