Drug resistance occurred in a newly characterized preclinical model of lung cancer brain metastasis.
Animals
Antineoplastic Agents
/ therapeutic use
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Brain Neoplasms
/ drug therapy
Cell Line, Tumor
Cisplatin
/ therapeutic use
Drug Resistance, Neoplasm
ErbB Receptors
/ genetics
Etoposide
/ therapeutic use
Female
Gefitinib
/ therapeutic use
Gene Expression Regulation, Neoplastic
Humans
Lung Neoplasms
/ pathology
Mice
Mice, Nude
Pemetrexed
/ therapeutic use
Xenograft Model Antitumor Assays
Brain metastasis
Drug resistance
EGFR-TKI
PC-9
Journal
BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800
Informations de publication
Date de publication:
07 Apr 2020
07 Apr 2020
Historique:
received:
17
12
2019
accepted:
30
03
2020
entrez:
9
4
2020
pubmed:
9
4
2020
medline:
2
1
2021
Statut:
epublish
Résumé
Cancer metastasis and drug resistance have traditionally been studied separately, though these two lethal pathological phenomena almost always occur concurrently. Brain metastasis occurs in a large proportion of lung cancer patients (~ 30%). Once diagnosed, patients have a poor prognosis surviving typically less than 1 year due to lack of treatment efficacy. Human metastatic lung cancer cells (PC-9-Br) were injected into the left cardiac ventricle of female athymic nude mice. Brain lesions were allowed to grow for 21 days, animals were then randomized into treatment groups and treated until presentation of neurological symptoms or when moribund. Prior to tissue collection mice were injected with Oregon Green and A PC-9 brain seeking line (PC-9-Br) was established. Mice inoculated with PC-9-Br resulted in a decreased survival time compared with mice inoculated with parental PC-9. Non-targeted chemotherapy with cisplatin and etoposide (51.5 days) significantly prolonged survival of PC-9-Br brain metastases in mice compared to vehicle control (42 days) or cisplatin and pemetrexed (45 days). Further in-vivo imaging showed greater tumor vasculature in mice treated with cisplatin and etoposide compared to non-tumor regions, which was not observed in mice treated with vehicle or cisplatin and pemetrexed. More importantly, PC-9-Br showed significant resistance to gefitinib by in-vitro MTT assays (IC50 > 2.5 μM at 48 h and 0.1 μM at 72 h) compared with parental PC-9 (IC50: 0.75 μM at 48 h and 0.027 μM at 72 h). Further studies on the molecular mechanisms of gefitinib resistance revealed that EGFR and phospho-EGFR were significantly decreased in PC-9-Br compared with PC-9. Expression of E-cadherin and vimentin did not show EMT in PC-9-Br compared with parental PC-9, and PC-9-Br had neither a T790M mutation nor amplifications of MET and HER2 compared with parental PC-9. Our study demonstrated that brain metastases of lung cancer cells may independently prompt drug resistance without drug treatment.
Sections du résumé
BACKGROUND
BACKGROUND
Cancer metastasis and drug resistance have traditionally been studied separately, though these two lethal pathological phenomena almost always occur concurrently. Brain metastasis occurs in a large proportion of lung cancer patients (~ 30%). Once diagnosed, patients have a poor prognosis surviving typically less than 1 year due to lack of treatment efficacy.
METHODS
METHODS
Human metastatic lung cancer cells (PC-9-Br) were injected into the left cardiac ventricle of female athymic nude mice. Brain lesions were allowed to grow for 21 days, animals were then randomized into treatment groups and treated until presentation of neurological symptoms or when moribund. Prior to tissue collection mice were injected with Oregon Green and
RESULTS
RESULTS
A PC-9 brain seeking line (PC-9-Br) was established. Mice inoculated with PC-9-Br resulted in a decreased survival time compared with mice inoculated with parental PC-9. Non-targeted chemotherapy with cisplatin and etoposide (51.5 days) significantly prolonged survival of PC-9-Br brain metastases in mice compared to vehicle control (42 days) or cisplatin and pemetrexed (45 days). Further in-vivo imaging showed greater tumor vasculature in mice treated with cisplatin and etoposide compared to non-tumor regions, which was not observed in mice treated with vehicle or cisplatin and pemetrexed. More importantly, PC-9-Br showed significant resistance to gefitinib by in-vitro MTT assays (IC50 > 2.5 μM at 48 h and 0.1 μM at 72 h) compared with parental PC-9 (IC50: 0.75 μM at 48 h and 0.027 μM at 72 h). Further studies on the molecular mechanisms of gefitinib resistance revealed that EGFR and phospho-EGFR were significantly decreased in PC-9-Br compared with PC-9. Expression of E-cadherin and vimentin did not show EMT in PC-9-Br compared with parental PC-9, and PC-9-Br had neither a T790M mutation nor amplifications of MET and HER2 compared with parental PC-9.
CONCLUSION
CONCLUSIONS
Our study demonstrated that brain metastases of lung cancer cells may independently prompt drug resistance without drug treatment.
Identifiants
pubmed: 32264860
doi: 10.1186/s12885-020-06808-2
pii: 10.1186/s12885-020-06808-2
pmc: PMC7137432
doi:
Substances chimiques
Antineoplastic Agents
0
Pemetrexed
04Q9AIZ7NO
Etoposide
6PLQ3CP4P3
EGFR protein, human
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
Cisplatin
Q20Q21Q62J
Gefitinib
S65743JHBS
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
292Subventions
Organisme : NIGMS NIH HHS
ID : P20GM121322
Pays : United States
Organisme : NIGMS NIH HHS
ID : U54 GM104942
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM121322
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM103434
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20GM103434
Pays : United States
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