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Anti-tumor effect of CDK inhibitors on CDKN2A-defective squamous cell lung cancer cells

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Abstract

Background

Squamous cell lung cancer (SqCLC) is a distinct histologic subtype of non-small cell lung cancer (NSCLC). Although the discovery of driver mutations and their targeted drugs has remarkably improved the treatment outcomes for lung adenocarcinoma, currently no such molecular target is clinically available for SqCLC. The CDKN2A locus at 9p21 encodes two alternatively spliced proteins, p16INK4a (p16) and p14ARF (p14), which function as cell cycle inhibitors. The Cancer Genome Atlas (TCGA) project revealed that CDKN2A is inactivated in 72% of SqCLC cases. In addition, it was found that CDKN2A mutations are significantly more common in SqCLC than in adenocarcinoma. Down-regulation of p16 and p14 by CDKN2A gene inactivation leads to activation of cyclin-dependent kinases (CDKs), thereby permitting constitutive phosphorylation of Rb and subsequent cell cycle progression. Here, we hypothesized that CDK inhibition may serve as an attractive strategy for the treatment of CDKN2A-defective SqCLC.

Methods

We investigated whether the CDK inhibitors flavopiridol and dinaciclib may exhibit antitumor activity in CDKN2A-defective SqCLC cells compared to control cells. The cytotoxic effect of the CDK inhibitors was evaluated using cell viability assays, and the induction of apoptosis was assessed using TUNEL assays and Western blot analyses. Finally, anti-tumor effects of the CDK inhibitors on xenografted cells were investigated in vivo.

Results

We found that flavopiridol and dinaciclib induced cytotoxicity by enhancing apoptosis in CDKN2A-defective SqCLC cells, and that epithelial to mesenchymal transition (EMT) decreased and autophagy increased during this process. In addition, we found that autophagy had a cytoprotective role.

Conclusion

Our data suggest a potential role of CDK inhibitors in managing CDKN2A-defective SqCLC.

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Acknowledgements

This study was supported by a grant from the Korea Institute of Radiological and Medical Sciences (KIRAMS), funded by Ministry of Science and ICT (MSIT), Republic of Korea (50474-2018).

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Authors and Affiliations

  1. Division of Pulmonology, Department of Internal Medicine, Korea Cancer Center Hospital, 75 Nowon-Ro, Nowon-Gu, Seoul, 01812, South Korea

    Eun-Hui Jeong, Tae-Gul Lee, Yun Jung Ko, Seo Yun Kim, Hye-Ryoun Kim & Cheol Hyeon Kim

  2. School of Life Sciences and Biotechnology, Korea University, Seoul, South Korea

    Tae-Gul Lee & Hyunggee Kim

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  1. Eun-Hui Jeong
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Jeong, EH., Lee, TG., Ko, Y.J. et al. Anti-tumor effect of CDK inhibitors on CDKN2A-defective squamous cell lung cancer cells. Cell Oncol. 41, 663–675 (2018). https://doi.org/10.1007/s13402-018-0404-6

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