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Research Article
Masahiro Seike
Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School
Corresponding Author
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Overcoming acquired resistance to the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib is currently an important clinical issue in treating EGFR-mutant non-small cell lung cancer (NSCLC) patients. EGFR-TKI may synergize with chemotherapy and offer novel treatment strategies for overcoming acquired resistance. Here, we evaluate the therapeutic potential of combining osimertinib with pemetrexed and clarify the underlying molecular mechanisms. Gene expression microarrays were used to assess gene expression on exposure to osimertinib in the presence or absence of pemetrexed and we established cell lines resistant to osimertinib as well as those resistant to osimertinib+pemetrexed in order to explore mechanisms of resistance. Osimertinib+pemetrexed treatment significantly delayed the emergence of resistance relative to monotherapy in vitro and in vivo. Microarray analysis revealed significantly downregulated expression of the anti-apoptotic gene PLK1 in cells treated with osimertinib+pemetrexed. Consistent with this, cell lines resistant to osimertinib or to osimertinib+pemetrexed, exhibited overexpression of PLK1. Accordingly, PLK1 inhibition by siRNA or PLK1 inhibitor volasertib inhibited proliferation by inducing apoptosis in these resistant cell lines. Blocking PLK1 contributes to mediating the synergistic antiproliferative effect of osimertinib+pemetrexed in EGFR-mutant NSCLC cells. PLK1 overexpression may be a critical mechanism responsible for the acquired resistance of such mutants to osimertinib+pemetrexed.
Keywords
Non-small-cell lung cancer, Epidermal growth factor receptor, Osimertinib, Pemetrexed, Polo-like kinase 1
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Competing interest reported. This study was supported in part by a Clinical Rebiopsy Bank Project for Comprehensive Cancer Therapy Development from Ministry of Education, Culture, Sports, Science and Technology Supported Program for the Strategic Research Foundation at Private Universities (to A.G and M.S). M.S has received a commercial research grant from Eli Lilly Japan K.K and has received speakers’ bureau honoraria from AstraZeneca and Eli Lilly Japan K.K.
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This is a preprint. It has not completed peer review.
Research Article
Masahiro Seike
Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
History
CURRENT STATUS: Posted
Version 1
Posted 11 Mar, 2021
No community comments so far
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Overcoming acquired resistance to the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib is currently an important clinical issue in treating EGFR-mutant non-small cell lung cancer (NSCLC) patients. EGFR-TKI may synergize with chemotherapy and offer novel treatment strategies for overcoming acquired resistance. Here, we evaluate the therapeutic potential of combining osimertinib with pemetrexed and clarify the underlying molecular mechanisms. Gene expression microarrays were used to assess gene expression on exposure to osimertinib in the presence or absence of pemetrexed and we established cell lines resistant to osimertinib as well as those resistant to osimertinib+pemetrexed in order to explore mechanisms of resistance. Osimertinib+pemetrexed treatment significantly delayed the emergence of resistance relative to monotherapy in vitro and in vivo. Microarray analysis revealed significantly downregulated expression of the anti-apoptotic gene PLK1 in cells treated with osimertinib+pemetrexed. Consistent with this, cell lines resistant to osimertinib or to osimertinib+pemetrexed, exhibited overexpression of PLK1. Accordingly, PLK1 inhibition by siRNA or PLK1 inhibitor volasertib inhibited proliferation by inducing apoptosis in these resistant cell lines. Blocking PLK1 contributes to mediating the synergistic antiproliferative effect of osimertinib+pemetrexed in EGFR-mutant NSCLC cells. PLK1 overexpression may be a critical mechanism responsible for the acquired resistance of such mutants to osimertinib+pemetrexed.
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