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Third generation EGFR inhibitor osimertinib combined with pemetrexed or cisplatin exerts long-lasting anti-tumor effect in EGFR-mutated pre-clinical models of NSCLC
- Source :
- Journal of Experimental & Clinical Cancer Research, Vol 38, Iss 1, Pp 1-12 (2019), Journal of Experimental & Clinical Cancer Research : CR
- Publication Year :
- 2019
- Publisher :
- BMC, 2019.
-
Abstract
- Background The third generation Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) osimertinib has been initially approved for T790M positive Non-Small Cell Lung Cancer (NSCLC) and more recently for first-line treatment of EGFR-mutant T790M negative NSCLC patients. Similarly to previous generation TKIs, despite the high response rate, disease progression eventually occurs and current clinical research is focused on novel strategies to delay the emergence of osimertinib resistance. In this study we investigated the combination of osimertinib with pemetrexed or cisplatin in EGFR-mutated NSCLC cell lines and xenografts. Methods Tumor growth was evaluated in a PC9T790M xenograft model and tissue composition was morphometrically determined. PC9, PC9T790M and HCC827 cell lines were employed to test the efficacy of osimertinib and chemotherapy combination in vitro. Cell viability and cell death were evaluated by MTT assay and fluorescence microscopy. Protein expression and gene status were analysed by Western blotting, fluorescence in situ hybridization analysis, next-generation sequencing and digital droplet PCR. Results In xenograft models, osimertinib significantly inhibited tumor growth, however, as expected, in 50% of mice drug-resistance developed. A combination of osimertinib with pemetrexed or cisplatin prevented or at least delayed the onset of resistance. Interestingly, such combinations increased the fraction of fibrotic tissue and exerted a long-lasting activity after stopping therapy. In vitro studies demonstrated the stronger efficacy of the combination over the single treatments in inhibiting cell proliferation and inducing cell death in PC9T790M cells as well as in T790M negative PC9 and HCC827 cell lines, suggesting the potential role of this strategy also as first-line treatment. Finally, we demonstrated that osimertinib resistant clones, either derived from resistant tumors or generated in vitro, were less sensitive to pemetrexed prompting to use a chemotherapy regimen non-containing pemetrexed in patients after progression to osimertinib treatment. Conclusions Our results identify a combination between osimertinib and pemetrexed or cisplatin potentially useful in the treatment of EGFR-mutated NSCLC patients, which might delay the appearance of osimertinib resistance with long-lasting effects. Electronic supplementary material The online version of this article (10.1186/s13046-019-1240-x) contains supplementary material, which is available to authorized users.
- Subjects :
- 0301 basic medicine
Cancer Research
Lung Neoplasms
Resistance
Drug Resistance
Epidermal Growth Factor Receptor
Tyrosine-kinase inhibitor
T790M
Mice
0302 clinical medicine
Carcinoma, Non-Small-Cell Lung
Osimertinib
Epidermal growth factor receptor
Non-Small-Cell Lung
EGFR inhibitors
Aniline Compounds
Tumor
biology
Drug Synergism
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Chemotherapy regimen
Gene Expression Regulation, Neoplastic
ErbB Receptors
Pemetrexed
Oncology
030220 oncology & carcinogenesis
Female
medicine.drug
medicine.drug_class
Cell Survival
lcsh:RC254-282
Cell Line
03 medical and health sciences
Cell Line, Tumor
medicine
Animals
Humans
Cisplatin
Non-Small Cell Lung Cancer
Acrylamides
Cell Proliferation
Drug Resistance, Neoplasm
Mutation
Xenograft Model Antitumor Assays
Neoplastic
business.industry
Research
Carcinoma
030104 developmental biology
Gene Expression Regulation
Cancer research
biology.protein
Neoplasm
business
Subjects
Details
- Language :
- English
- ISSN :
- 17569966
- Volume :
- 38
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Journal of Experimental & Clinical Cancer Research
- Accession number :
- edsair.doi.dedup.....16adb6cae73c4e3017506561f7243aba