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Osimertinib and pterostilbene in EGFR-mutation-positive non-small cell lung cancer (NSCLC)
- Source :
- International Journal of Biological Sciences, r-IGTP. Repositorio Institucional de Producción Científica del Instituto de Investigación Germans Trias i Pujol, instname, International Journal of Biological sciences
- Publication Year :
- 2019
-
Abstract
- Monotherapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) still leads to incomplete responses in most EGFR-mutation positive non-small cell lung cancer (NSCLC) patients, often due to acquired resistance through activation of parallel compensatory pathways. We have previously shown that co-targeting EGFR, signal transducer and activator of transcription 3 (STAT3), and Src-yes-associated protein 1 (YAP1) was highly synergistic in vitro and in vivo. In the present study, we treated EGFR-mutation positive cell lines with the combination of osimertinib plus a natural compound, pterostilbene, which has been reported to abrogate Src and STAT3 activation. Methods: Cell viability assays and immunoblotting were performed to reveal the mechanisms of action of pterostilbene, osimertinib and pterostilbene plus osimertinib in five EGFR-mutation positive NSCLC and one triple negative breast cancer (TNBC) cell lines. Results: Osimertinib plus pterostilbene yielded synergistic effects in all EGFR-mutation positive NSCLC cell lines investigated. Surprisingly, pterostilbene alone did not inhibit, nor downregulate Src phosphorylation in the EGFR-mutation positive NSCLC cell lines or the TNBC cell line, MDA-MB-231. However, the double combination of osimertinib plus pterostilbene reversed the osimertinib-induced STAT3, YAP1, and CUB domain-containing protein-1 (CDCP1) phosphorylation and slightly suppressed Src phosphorylation in PC9 and H1975 cells. Conclusion: The results of this study indicate that pterostilbene may be used to abrogate the activated resistance pathways of single osimertinib treatment in EGFR-mutation positive NSCLC. Future studies should focus on in vivo translation and confirmation of these results.
- Subjects :
- STAT3 Transcription Factor
Pterostilbene
therapy resistance
non-small cell lung cancer (NSCLC)
Antineoplastic Agents
Triple Negative Breast Neoplasms
NSCLC
Applied Microbiology and Biotechnology
03 medical and health sciences
chemistry.chemical_compound
Antigens, Neoplasm
Carcinoma, Non-Small-Cell Lung
Cell Line, Tumor
Stilbenes
medicine
Humans
Osimertinib
Epidermal growth factor receptor
Phosphorylation
Molecular Biology
Ecology, Evolution, Behavior and Systematics
Triple-negative breast cancer
030304 developmental biology
Adaptor Proteins, Signal Transducing
0303 health sciences
Acrylamides
Aniline Compounds
biology
Chemistry
Drug Synergism
YAP-Signaling Proteins
Cell Biology
medicine.disease
3. Good health
ErbB Receptors
Drug Resistance, Neoplasm
osimertinib
Cancer research
biology.protein
CDCP1
Tyrosine kinase
Cell Adhesion Molecules
Developmental Biology
Proto-oncogene tyrosine-protein kinase Src
Transcription Factors
Research Paper
Subjects
Details
- ISSN :
- 14492288
- Volume :
- 15
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- International journal of biological sciences
- Accession number :
- edsair.doi.dedup.....dcda7bdc59a4fd95f3ec40d39464b96c