Journal
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
Volume 15, Issue 12, Pages 2607-2614Publisher
IVYSPRING INT PUBL
DOI: 10.7150/ijbs.32889
Keywords
Pterostilbene; NSCLC; osimertinib; therapy resistance
Categories
Funding
- La Caixa Foundation
- Marie Sklodowska-Curie Innovative Training Networks European Grant (ELBA) [765492]
- Marie Sklodowska-Curie Research and Innovation Program Grant (TECHNIOspring PLUS)
- Spanish Association Against Cancer (AECC) grant [PROYE18012ROSE]
- Instituto de Salud Carlos III grant (RESPONSE) [PIE16/00011]
- Instituto de Salud Carlos III grant [PI14/01678]
- Agency for Business Competitiveness of the Government of Catalonia Grant
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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.
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