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CDK7 inhibition as a promising therapeutic strategy for lung squamous cell carcinomas with a SOX2 amplification

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Abstract

Purpose

Despite the development of molecular targeted therapies, few advances have been made in the treatment of lung squamous cell carcinoma (SCC). SOX2 amplification is one of the most common genetic alterations in SCC. Here, we investigated the effects of THZ1, a potent cyclin-dependent kinase 7 (CDK7) inhibitor that plays a key role in gene transcription, in SCC.

Methods

Lung SCC-derived cell viabilities were assessed using a CCK-8 assay. SOX2 expression and RNAPII-CTD phosphorylation levels after THZ1 treatment were determined by Western blotting. The effect of SOX2 suppression using shRNA was assessed by flow cytometry. Gene expression patterns after THZ1 treatment of lung SCC-derived cells were identified using microarray-based mRNA profiling.

Results

We found that THZ1 treatment led to suppression of cell growth and apoptotic cell death in SOX2-amplified SCC-derived cells only, whereas the modest growth-inhibitory effect of cisplatin did not differ according to SOX2 amplification status. We also found that THZ1 decreased the phosphorylation of the carboxyl-terminal domain of RNA polymerase II and the expression of several genes. Specifically, we found that the expression of transcription-associated genes, including SOX2, was down-regulated by THZ1 in SOX2-amplified SCC cells. This inhibition of SOX2 expression resulted in suppression of the growth of these cells.

Conclusions

From our data, we conclude that THZ1 may effectively control the proliferation and survival of SOX2-amplified SCC cells through a decrease in global transcriptional activity, suggesting that CDK7 inhibition leading to transcription suppression may be a promising therapeutic option for lung SCC with a SOX2 amplification.

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Financial support

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2015R1DA1A01057022 to JKR) and a grant (2016–689 to HRK and 2016–709 to JCL) from the Asan Institute for Life Sciences, Seoul, Korea.

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Author notes

  1. Jae Young Hur and Hyeong Ryul Kim contributed equally to this work.

Authors and Affiliations

  1. Asan Institute for Life Sciences, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea

    Jae Young Hur

  2. Lung Cancer Center & Department of Pathology, Konkuk University Medical Center, Seoul, South Korea

    Jae Young Hur

  3. Department of Thoracic and Cardiovascular Surgery, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea

    Hyeong Ryul Kim

  4. Department of Internal Medicine, Graduate School, Chungbuk National University, Cheongju, South Korea

    Jung Yeon Lee

  5. Department of Pulmonology and Critical Care Medicine, Asan Medical Center, College of Medicine, University of Ulsan, Seoul, South Korea

    Sojung Park, Ji An Hwang, Woo Sung Kim & Chang-Min Choi

  6. Department of Oncology, Asan Medical Center, College of Medicine, University of Ulsan, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea

    Shinkyo Yoon, Chang-Min Choi & Jae Cheol Lee

  7. Department of Convergence Medicine, Asan Medical Center, College of Medicine, University of Ulsan, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea

    Jin Kyung Rho

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Contributions

JYH, HRK, JKR and JCL conceived and designed the study. JYH performed the experiments. JYH, HRK, JKR, JYL, SP, JAH, WSK, SY and C-MC analyzed the data. JYH, JKR and JCL wrote the manuscript. All authors reviewed and approved the final version of the manuscript.

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Correspondence to Jin Kyung Rho or Jae Cheol Lee.

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Hur, J.Y., Kim, H.R., Lee, J.Y. et al. CDK7 inhibition as a promising therapeutic strategy for lung squamous cell carcinomas with a SOX2 amplification. Cell Oncol. 42, 449–458 (2019). https://doi.org/10.1007/s13402-019-00434-2

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