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Cyclin-dependent kinase (CDK) 4/6 inhibition in non-small cell lung cancer with epidermal growth factor receptor (EGFR) mutations

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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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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

EGFR:

Epidermal growth factor receptor

TKI:

Tyrosine kinase inhibitor

CDK:

Cyclin- dependent kinase

CI:

Combination index

Fa:

Fraction affected

EdU:

5-ethynyl-2’-deoxyuridine

HER2:

Human epidermal growth factor 2

MST:

Median survival time

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Acknowledgements

The authors would like to thank Dr. Brian Quinn for his critical comments on the manuscript and Ms. Kaori Ogata for her technical support for the experiments. This work was supported by KAKENHI (Grant Number JP 21K08889 and 20K09168), Japan Society for the Promotion of Science, Tokyo, Japan.

Funding

This work was supported by KAKENHI (Grant Number JP 21K08889 and 20K09168), Japan Society for the Promotion of Science, Tokyo, Japan.

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Authors and Affiliations

  1. Department of Thoracic and Breast Surgery, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, 879-5593, Yufu, Japan

    Atsushi Osoegawa, Yohei Takumi, Takafumi Hashimoto, Shotaro Nakatsuji, Mayu Hori, Mayu Sakai, Takashi Karashima, Miyuki Abe, Michiyo Miyawaki & Kenji Sugio

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  1. Atsushi Osoegawa
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Atsushi Osoegawa, Yohei Takumi, Takafumi Hashimoto, Shotaro Nakatsuji, Mayu Hori, Mayu Sakai, Takashi Karashima, Miyuki Abe, Michiyo Miyawaki, and Kenji Sugio. The first draft of the manuscript was written by Atsushi Osoegawa and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Atsushi Osoegawa.

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Ethics approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the internal review board of Oita University Faculty of Medicine (IRB No. 698).

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Informed consent was obtained from all individual participants included in the study.

Financial interests

Yohei Takumi, Takafumi Hashimoto, Shotaro Nakatsuji, Mayu Hori, Mayu Sakai, Takashi Karashima, Miyuki Abe, and Michiyo Miyawaki declare they have no financial interests. Atsushi Osoegawa and Kenji Sugio have received speaker and consultant honoraria from AstraZeneca (Cambridge, UK).

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Osoegawa, A., Takumi, Y., Hashimoto, T. et al. Cyclin-dependent kinase (CDK) 4/6 inhibition in non-small cell lung cancer with epidermal growth factor receptor (EGFR) mutations. Invest New Drugs 41, 183–192 (2023). https://doi.org/10.1007/s10637-023-01337-8

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