Cyclin-dependent kinase (CDK) 4/6 inhibition in non-small cell lung cancer with epidermal growth factor receptor (EGFR) mutations
Abstract Background: Lung cancer is the leading cause of cancer death worldwide, and EGFR mutation is the most common genetic alteration among Asian patients with lung adenocarcinoma. While osimertinib has been shown to be effective in lung cancer patients with EGFR mutation, the majority of patients eventually develop acquired resistance to treatment. We explored the significance of the cyclin D1 expression in patients with EGFR mutation and the potential efficacy of adding abemaciclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, simultaneously with osimertinib in vitro. Materials and methods: Immunohistochemical staining, using an anti-cyclin D1 antibody, of specimens from 83 patients with EGFR mutation (male, n = 27; pStage 0-I, n = 71) who were treated by surgical resection between 2017 and 2020, and the relationship between the cyclin D1 expression and clinicopathological factors was analyzed. Additionally, the combined effect of osimertinib and abemaciclib in lung cancer cell lines were analyzed using a growth inhibition test, and the signaling pathway underlying the combined effect was investigated. Results: Cyclin D1 was negative in 18.1% of patients with EGFR mutation, and cyclin D1 negativity was associated with pStage ≥ II (p = 0.02), lymph node metastasis (p = 0.001), and lymphatic invasion (p = 0.01). The cyclin D1-negative group had significantly shorter recurrence-free survival (p = 0.02), although this difference disappeared when limited to pN0 patients. In EGFR mutated cell lines, the combination of osimertinib and abemaciclib demonstrated synergistic effects, which were thought to be mediated by the inhibition of AKT phosphorylation. Conclusion: Combination therapy with CDK4/6 inhibitors and EGFR-TKIs may be a promising approach..
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:41 |
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| Enthalten in: |
Investigational new drugs - 41(2023), 2 vom: 15. Feb., Seite 183-192 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Osoegawa, Atsushi [VerfasserIn] |
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| Links: |
Volltext [lizenzpflichtig] |
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| Themen: |
Cell cycle |
| Anmerkungen: |
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law. |
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| doi: |
10.1007/s10637-023-01337-8 |
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| 520 | |a Abstract Background: Lung cancer is the leading cause of cancer death worldwide, and EGFR mutation is the most common genetic alteration among Asian patients with lung adenocarcinoma. While osimertinib has been shown to be effective in lung cancer patients with EGFR mutation, the majority of patients eventually develop acquired resistance to treatment. We explored the significance of the cyclin D1 expression in patients with EGFR mutation and the potential efficacy of adding abemaciclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, simultaneously with osimertinib in vitro. Materials and methods: Immunohistochemical staining, using an anti-cyclin D1 antibody, of specimens from 83 patients with EGFR mutation (male, n = 27; pStage 0-I, n = 71) who were treated by surgical resection between 2017 and 2020, and the relationship between the cyclin D1 expression and clinicopathological factors was analyzed. Additionally, the combined effect of osimertinib and abemaciclib in lung cancer cell lines were analyzed using a growth inhibition test, and the signaling pathway underlying the combined effect was investigated. Results: Cyclin D1 was negative in 18.1% of patients with EGFR mutation, and cyclin D1 negativity was associated with pStage ≥ II (p = 0.02), lymph node metastasis (p = 0.001), and lymphatic invasion (p = 0.01). The cyclin D1-negative group had significantly shorter recurrence-free survival (p = 0.02), although this difference disappeared when limited to pN0 patients. In EGFR mutated cell lines, the combination of osimertinib and abemaciclib demonstrated synergistic effects, which were thought to be mediated by the inhibition of AKT phosphorylation. Conclusion: Combination therapy with CDK4/6 inhibitors and EGFR-TKIs may be a promising approach. | ||
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| 700 | 1 | |a Abe, Miyuki |4 aut | |
| 700 | 1 | |a Miyawaki, Michiyo |4 aut | |
| 700 | 1 | |a Sugio, Kenji |4 aut | |
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