Differential therapeutic effects of PARP and ATR inhibition combined with radiotherapy in the treatment of subcutaneous versus orthotopic lung tumour models.
Animals
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Ataxia Telangiectasia Mutated Proteins
/ antagonists & inhibitors
Carcinoma, Lewis Lung
/ drug therapy
Checkpoint Kinase 1
/ metabolism
Chemoradiotherapy
Female
Indoles
Lung Neoplasms
/ drug therapy
Mice
Mice, Inbred C57BL
Morpholines
Phthalazines
/ administration & dosage
Piperazines
/ administration & dosage
Poly(ADP-ribose) Polymerase Inhibitors
/ administration & dosage
Protein Kinase Inhibitors
/ administration & dosage
Pyrimidines
/ administration & dosage
Signal Transduction
/ drug effects
Sulfonamides
Sulfoxides
/ administration & dosage
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
09 2020
09 2020
Historique:
received:
15
08
2019
accepted:
21
05
2020
revised:
30
04
2020
pubmed:
18
6
2020
medline:
1
4
2021
entrez:
18
6
2020
Statut:
ppublish
Résumé
Subcutaneous mouse tumour models are widely used for the screening of novel antitumour treatments, although these models are poor surrogate models of human cancers. We compared the antitumour efficacy of the combination of ionising radiation (IR) with two DNA damage response inhibitors, the PARP inhibitor olaparib and the ATR inhibitor AZD6738 (ceralasertib), in subcutaneous versus orthotopic cancer models. Olaparib delayed the growth of irradiated Lewis lung carcinoma (LL2) subcutaneous tumours, in agreement with previous reports in human cell lines. However, the olaparib plus IR combination showed a very narrow therapeutic window against LL2 lung orthotopic tumours, with nearly no additional antitumour effect compared with that of IR alone, and tolerability issues emerged at high doses. The addition of AZD6738 greatly enhanced the efficacy of the olaparib plus IR combination treatment against subcutaneous but not orthotopic LL2 tumours. Moreover, olaparib plus AZD6738 administration concomitant with IR even worsened the response to radiation of head and neck orthotopic tumours and induced mucositis. These major differences in the responses to treatments between subcutaneous and orthotopic models highlight the importance of using more pathologically relevant models, such as syngeneic orthotopic models, to determine the most appropriate therapeutic approaches for translation to the clinic.
Sections du résumé
BACKGROUND
Subcutaneous mouse tumour models are widely used for the screening of novel antitumour treatments, although these models are poor surrogate models of human cancers.
METHODS
We compared the antitumour efficacy of the combination of ionising radiation (IR) with two DNA damage response inhibitors, the PARP inhibitor olaparib and the ATR inhibitor AZD6738 (ceralasertib), in subcutaneous versus orthotopic cancer models.
RESULTS
Olaparib delayed the growth of irradiated Lewis lung carcinoma (LL2) subcutaneous tumours, in agreement with previous reports in human cell lines. However, the olaparib plus IR combination showed a very narrow therapeutic window against LL2 lung orthotopic tumours, with nearly no additional antitumour effect compared with that of IR alone, and tolerability issues emerged at high doses. The addition of AZD6738 greatly enhanced the efficacy of the olaparib plus IR combination treatment against subcutaneous but not orthotopic LL2 tumours. Moreover, olaparib plus AZD6738 administration concomitant with IR even worsened the response to radiation of head and neck orthotopic tumours and induced mucositis.
CONCLUSIONS
These major differences in the responses to treatments between subcutaneous and orthotopic models highlight the importance of using more pathologically relevant models, such as syngeneic orthotopic models, to determine the most appropriate therapeutic approaches for translation to the clinic.
Identifiants
pubmed: 32546832
doi: 10.1038/s41416-020-0931-6
pii: 10.1038/s41416-020-0931-6
pmc: PMC7463250
doi:
Substances chimiques
Indoles
0
Morpholines
0
Phthalazines
0
Piperazines
0
Poly(ADP-ribose) Polymerase Inhibitors
0
Protein Kinase Inhibitors
0
Pyrimidines
0
Sulfonamides
0
Sulfoxides
0
ceralasertib
85RE35306Z
Atr protein, mouse
EC 2.7.1.-
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
Checkpoint Kinase 1
EC 2.7.11.1
Chek1 protein, mouse
EC 2.7.11.1
olaparib
WOH1JD9AR8
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
762-771Références
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