Pulsatile MEK Inhibition Improves Anti-tumor Immunity and T Cell Function in Murine Kras Mutant Lung Cancer.
Animals
Benzimidazoles
/ pharmacology
CD4-Positive T-Lymphocytes
/ cytology
CD8-Positive T-Lymphocytes
/ cytology
CTLA-4 Antigen
/ metabolism
Carcinoma, Non-Small-Cell Lung
/ drug therapy
Disease Models, Animal
Female
Humans
Lung Neoplasms
/ drug therapy
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Programmed Cell Death 1 Receptor
/ metabolism
Protein Kinase Inhibitors
/ pharmacology
Proto-Oncogene Proteins p21(ras)
/ genetics
Pyridones
/ pharmacology
Pyrimidinones
/ pharmacology
Survival Rate
T-Lymphocytes
/ cytology
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
16 04 2019
16 04 2019
Historique:
received:
26
07
2018
revised:
01
02
2019
accepted:
18
03
2019
entrez:
18
4
2019
pubmed:
18
4
2019
medline:
17
6
2020
Statut:
ppublish
Résumé
KRAS is one of the driver oncogenes in non-small-cell lung cancer (NSCLC) but remains refractory to current modalities of targeted pathway inhibition, which include inhibiting downstream kinase MEK to circumvent KRAS activation. Here, we show that pulsatile, rather than continuous, treatment with MEK inhibitors (MEKis) maintains T cell activation and enables their proliferation. Two MEKis, selumetinib and trametinib, induce T cell activation with increased CTLA-4 expression and, to a lesser extent, PD-1 expression on T cells in vivo after cyclical pulsatile MEKi treatment. In addition, the pulsatile dosing schedule alone shows superior anti-tumor effects and delays the emergence of drug resistance. Furthermore, pulsatile MEKi treatment combined with CTLA-4 blockade prolongs survival in mice bearing tumors with mutant Kras. Our results set the foundation and show the importance of a combinatorial therapeutic strategy using pulsatile targeted therapy together with immunotherapy to optimally enhance tumor delay and promote long-term anti-tumor immunity.
Identifiants
pubmed: 30995478
pii: S2211-1247(19)30396-1
doi: 10.1016/j.celrep.2019.03.066
pmc: PMC6719696
mid: NIHMS1527189
pii:
doi:
Substances chimiques
AZD 6244
0
Benzimidazoles
0
CTLA-4 Antigen
0
Pdcd1 protein, mouse
0
Programmed Cell Death 1 Receptor
0
Protein Kinase Inhibitors
0
Pyridones
0
Pyrimidinones
0
trametinib
33E86K87QN
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
806-819.e5Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA166480
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA215136
Pays : United States
Informations de copyright
Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.
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