Osimertinib and pterostilbene in EGFR-mutation-positive non-small cell lung cancer (NSCLC)
Jillian Wilhelmina Paulina Bracht1, Niki Karachaliou1,2, Jordi Berenguer1
1Pangaea Oncology, Laboratory of Molecular Biology, Quirón-Dexeus University Institute, Barcelona, Spain.
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.
Insights
Combining osimertinib with pterostilbene shows synergistic effects against EGFR-mutation positive non-small cell lung cancer (NSCLC). This combination overcomes resistance by targeting STAT3 and YAP1 pathways, offering a potential new strategy for NSCLC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Monotherapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutation positive non-small cell lung cancer (NSCLC) often results in incomplete responses due to acquired resistance.
- Activation of parallel compensatory pathways, including signal transducer and activator of transcription 3 (STAT3) and Src-yes-associated protein 1 (YAP1), contributes to treatment resistance.
- Previous research indicated synergistic effects of co-targeting EGFR, STAT3, and YAP1.
Purpose of the Study:
- To investigate the efficacy of combining osimertinib with pterostilbene, a natural compound, in EGFR-mutation positive NSCLC cell lines.
- To elucidate the underlying mechanisms of action for the combination therapy.
- To determine if pterostilbene can abrogate resistance pathways activated by single-agent osimertinib treatment.
Main Methods:
- Cell viability assays and immunoblotting were employed to assess the effects of pterostilbene and osimertinib, alone and in combination.
- Experiments were conducted on five EGFR-mutation positive NSCLC cell lines and one triple-negative breast cancer (TNBC) cell line.
- Key signaling proteins including STAT3, YAP1, Src, and CDCP1 phosphorylation levels were analyzed.
Main Results:
- The combination of osimertinib and pterostilbene demonstrated synergistic effects across all tested EGFR-mutation positive NSCLC cell lines.
- Pterostilbene alone did not inhibit Src phosphorylation in NSCLC or TNBC cell lines.
- The combination therapy reversed osimertinib-induced phosphorylation of STAT3, YAP1, and CDCP1, and slightly suppressed Src phosphorylation.
Conclusions:
- Pterostilbene in combination with osimertinib shows promise in overcoming acquired resistance mechanisms in EGFR-mutation positive NSCLC.
- This combination therapy effectively targets key resistance pathways, suggesting a potential therapeutic strategy.
- Further in vivo studies are warranted to confirm these findings and explore clinical translation.
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